57 results on '"Brinda Emu"'
Search Results
2. Long-term quantitative assessment of anti-SARS-CoV-2 spike protein immunogenicity (QUASI) after COVID-19 vaccination in older people living with HIV (PWH)
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Jessica J. Tuan, Heidi Zapata, Lydia Barakat, Laurie Andrews, Anousheh Behnegar, Yee Won Kim, Jehanzeb Kayani, Suzana Mutic, Linda Ryall, Barbara Turcotte, Terese Critch-Gilfillan, Min Zhao, Syim Salahuddin, Shaili Gupta, Richard Sutton, Gerald Friedland, Brinda Emu, and Onyema Ogbuagu more...
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HIV ,COVID-19 ,SARS-CoV-2 ,Immunogenicity ,BNT162b2 ,Infectious and parasitic diseases ,RC109-216 - Abstract
Abstract Background The durability of immune responses to COVID-19 vaccines among older people living with HIV (PWH) is clinically important. Methods We aimed to assess vaccine-induced humoral immunity and durability in older PWH (≥ 55 years, n = 26) over 6 months (post-initial BNT162b2 series). A secondary and exploratory objective was to assess T-cell response and BNT162b2 booster reactogenicity, respectively. Our Visit 1 (3 weeks post-initial BNT162b2 dose) SARS-CoV-2 humoral immunity results are previously reported; these subjects were recruited for Visit 2 [2 weeks (+ 1 week window) post-second vaccination] and Visit 3 [6 months (± 2 week window) post-initial vaccination] in a single-center longitudinal observational study. Twelve participants had paired Visit 2/3 SARS-CoV-2 Anti-Spike IgG data. At Visit 3, SARS-CoV-2 Anti-Spike IgG testing occurred, and 5 subjects underwent T-cell immune response evaluation. Thereafter, subjects were offered BNT162b2 booster (concurrent day outside our study) per US FDA/CDC guidance; reactogenicity was assessed. The primary study outcome was presence of detectable Visit 3 SARS-CoV-2 Anti-Spike-1-RBD IgG levels. Secondary and exploratory outcomes were T-cell immune response and BNT162b2 booster reactogenicity, respectively. Wilcoxon signed-rank tests analyzed median SARS-CoV-2 Anti-Spike IgG 6-month trends. Results At Visit 3, 26 subjects underwent primary analysis with demographics noted: Median age 61 years; male n = 16 (62%), female n = 10 (38%); Black n = 13 (50%), White n = 13 (50%). Most subjects (n = 20, 77%) had suppressed HIV viremia on antiretroviral therapy, majority (n = 24, 92%) with CD4 > 200 cells/µL. At Visit 3, 26/26 (100%) had detectable Anti-Spike-1-RBD (≥ 0.8 U/mL). Among 12 subjects presenting to Visit 2/3, median SARS-CoV-2 Anti-Spike 1-RBD was 2087 U/mL at Visit 2, falling to 581.5 U/mL at Visit 3 (p = 0.0923), with a median 3.305-fold decrease over 6 months. Among subjects (n = 5) with 6-month T-cell responses measured, all had detectable cytokine-secreting anti-spike CD4 responses; 3 had detectable CD4 + Activation induced marker (AIM) + cells. Two had detectable cytokine-secreting CD8 responses, but all had positive CD8 + AIM + cells. Conclusions Among older PWH, SARS-CoV-2 Anti-Spike IgG and virus-specific T-cell responses are present 6 months post-primary BNT162b2 vaccination, and although waning, suggest retention of some degree of long-term protective immunity. more...
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- 2022
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3. Patients with HIV-associated cancers have evidence of increased T cell dysfunction and exhaustion prior to cancer diagnosis
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Anuradha Ganesan, Xun Wang, Yanhong Deng, Kurt A Schalper, Ryan C Maves, Brian Agan, Brinda Emu, Jason Okulicz, Omkar Chaudhary, Diane Trotta, Kaicheng Wang, Xiuping Chu, Chip Bradley, Karl Kronmann, Christina M Schofield, Jason M Blaylock, and Susan M Kaech more...
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2022
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4. Impact of illicit opioid use on T cell subsets among HIV-infected adults.
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E Jennifer Edelman, Kaku So-Armah, Debbie M Cheng, Margaret F Doyle, Sharon M Coleman, Carly Bridden, Natalia Gnatienko, Dmitry A Lioznov, Elena Blokhina, Matthew S Freiberg, Evgeny M Krupitsky, Brinda Emu, and Jeffrey H Samet more...
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Medicine ,Science - Abstract
OBJECTIVES:Opioids have immunosuppressive properties, yet opioid effects on T cell abnormalities consistent with the immune risk phenotype among HIV-infected individuals are understudied. METHODS:To assess associations between illicit opioid use and T cell characteristics (CD4/CD8 ratio, memory profiles based on CD45RO and CD28 expression, and senescence based on CD57 expression), we conducted an exploratory cross-sectional analysis of Russia ARCH, a cohort of antiretroviral therapy (ART)-naïve HIV-infected individuals recruited 11/2012 to 10/2014 in St. Petersburg, Russia. The main independent variable was past 30 day illicit opioid use (yes vs. no). Secondary analyses evaluated none (0 days), intermittent (1 to 7 days), and persistent (8 to 30 days) opioid use. Outcomes were determined with flow cytometry. Analyses were conducted using linear regression models. RESULTS:Among 186 participants, 38% reported any illicit opioid use (18% intermittent and 20% persistent). Any illicit opioid use was not significantly associated with T cell characteristics. Intermittent opioid use appeared to be associated with decreased memory CD8+ T cells proportion (CD45RO+CD45RA- CD8+ T cells: adjusted mean difference [AMD] [95% CI] = -6.15 [-11.50, -0.79], p = 0.02) and borderline significant increased senescent T cells (%CD57+ of total CD28-CD8+ T cells (AMD [95% CI] = 7.70 [-0.06, 15.46], p = 0.05). CONCLUSIONS:Among ART-naïve HIV-infected Russians, any illicit opioid use was not significantly associated with T cell abnormalities although intermittent illicit opioid use may be associated with CD8 T cell abnormalities. Longitudinal studies are warranted to confirm these findings given increased risk of infections and comorbidities seen among HIV-infected individuals with illicit opioid use. more...
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- 2017
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5. Composition and function of T cell subpopulations are slow to change despite effective antiretroviral treatment of HIV disease.
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Brinda Emu, Walter J Moretto, Rebecca Hoh, Melissa Krone, Jeffrey N Martin, Douglas F Nixon, Steven G Deeks, and Joseph M McCune
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Medicine ,Science - Abstract
The ability to reconstitute a normal immune system with antiretroviral therapy in the setting of HIV infection remains uncertain. This study aimed to characterize quantitative and qualitative aspects of various T cell subpopulations that do not improve despite effective ART. CD4∶CD8 ratio was evaluated in HIV-infected subjects with viral loads >10,000 copies/µl ("non-controllers", n = 42), those with undetectable viral loads on ART ("ART-suppressed", n = 53), and HIV-uninfected subjects (n = 22). In addition, T cell phenotype and function were examined in 25 non-controllers, 18 ART-suppressed, and 7 HIV-uninfected subjects. CD4∶CD8 ratio in non-controllers, ART-suppressed, and HIV-uninfected subjects was 0.25, 0.48, and 1.95 respectively (P more...
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- 2014
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6. A low T regulatory cell response may contribute to both viral control and generalized immune activation in HIV controllers.
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Peter W Hunt, Alan L Landay, Elizabeth Sinclair, Jeffrey A Martinson, Hiroyu Hatano, Brinda Emu, Philip J Norris, Michael P Busch, Jeffrey N Martin, Cicely Brooks, Joseph M McCune, and Steven G Deeks
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Medicine ,Science - Abstract
HIV-infected individuals maintaining undetectable viremia in the absence of therapy (HIV controllers) often maintain high HIV-specific T cell responses, which has spurred the development of vaccines eliciting HIV-specific T cell responses. However, controllers also often have abnormally high T cell activation levels, potentially contributing to T cell dysfunction, CD4+ T cell depletion, and non-AIDS morbidity. We hypothesized that a weak T regulatory cell (Treg) response might contribute to the control of viral replication in HIV controllers, but might also contribute to generalized immune activation, contributing to CD4+ T cell loss. To address these hypotheses, we measured frequencies of activated (CD38+ HLA-DR+), regulatory (CD4+CD25+CD127(dim)), HIV-specific, and CMV-specific T cells among HIV controllers and 3 control populations: HIV-infected individuals with treatment-mediated viral suppression (ART-suppressed), untreated HIV-infected "non-controllers" with high levels of viremia, and HIV-uninfected individuals. Despite abnormally high T cell activation levels, controllers had lower Treg frequencies than HIV-uninfected controls (P = 0.014). Supporting the propensity for an unusually low Treg response to viral infection in HIV controllers, we observed unusually high CMV-specific CD4+ T cell frequencies and a strong correlation between HIV-specific CD4+ T cell responses and generalized CD8+ T cell activation levels in HIV controllers (P ≤ 0.001). These data support a model in which low frequencies of Tregs in HIV controllers may contribute to an effective adaptive immune response, but may also contribute to generalized immune activation, potentially contributing to CD4 depletion. more...
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- 2011
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7. Human Immunodeficiency Virus Is Associated With Poor Overall Survival Among Patients With Head and Neck Cancer
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Syim Salahuddin, Oded Cohen, Margaret Wu, Javier Perez Irizarry, Teresita Vega, Geliang Gan, Yanhong Deng, Natalia Isaeva, Manju Prasad, Kurt A Schalper, Saral Mehra, Wendell G Yarbrough, and Brinda Emu more...
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Microbiology (medical) ,Infectious Diseases - Abstract
Background Head and neck squamous cell cancer (HNSCC) occurs at higher rates among persons with HIV (PWH). This study compares the impact of sociodemographic and clinicopathologic characteristics on outcomes among PWH-HNSCC compared with HNSCC patients without HIV. Methods Patient data from HNSCC individuals were collected at a single academic hospital center between 2002 and 2018. Forty-eight patients with HIV (HIV-HNSCC) and 2894 HNSCC patients without HIV were included. Multivariate analysis determined predictors of survival using Cox proportional hazards regression model. HIV-positive and -negative tumors were analyzed by quantitative immunofluorescence for expression of CD4, CD8, CD20 and PD-L1. Results HIV-HNSCC patients had a lower median overall survival than HNSCC patients without HIV (34 [18–84] vs 94 [86–103] months; P < .001). In multivariate analysis that included age, sex, race/ethnicity, stage, site, tobacco use, time to treatment initiation, and insurance status, HIV was an independent predictor of poorer survival, with a hazard ratio of 1.98 (95% CI: 1.32–2.97; P < .001). PWH with human papillomavirus (HPV)–positive oropharyngeal tumors also had worse prognosis than HPV-positive oropharyngeal tumors in the population without HIV (P < .001). The tumor microenvironment among HIV-HNSCC patients revealed lower intratumoral CD8 infiltration among HIV+ HPV+ tumors compared with HIV– HPV+ tumors (P = .04). Conclusions HIV-HNSCC patients had worse prognosis than the non-HIV population, with HIV being an independent predictor of poor clinical outcomes when accounting for important sociodemographic and clinicopathologic factors. Our findings highlight differences in tumor biology that require further detailed characterization in large cohorts and increased inclusion of PWH in immunotherapy trials. more...
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- 2022
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8. Serum Neutralizing Antibody Titers 12 Months After Coronavirus Disease 2019 Messenger RNA Vaccination: Correlation to Clinical Variables in an Adult, US Population
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Min Zhao, Rebecca Slotkin, Amar H Sheth, Lauren Pischel, Tassos C Kyriakides, Brinda Emu, Cynthia McNamara, Qiaosu Shi, Jaden Delgobbo, Jin Xu, Elizabeth Marhoffer, Aleagia Mercer-Falkoff, Jürgen Holleck, David Ardito, Richard E Sutton, and Shaili Gupta more...
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Microbiology (medical) ,Infectious Diseases - Abstract
Background We studied whether comorbid conditions affect strength and duration of immune responses after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) messenger RNA vaccination in a US-based, adult population. Methods Sera (before and after BNT162b2 vaccination) were tested serially up to 12 months after 2 doses of vaccine for SARS-CoV-2-anti-Spike neutralizing capacity by pseudotyping assay in 124 individuals; neutralizing titers were correlated to clinical variables with multivariate regression. Postbooster (third dose) effect was measured at 1 and 3 months in 72 and 88 subjects, respectively. Results After completion of primary vaccine series, neutralizing antibody half maximal inhibitory concentration (IC50) values were high at 1 month (14-fold increase from prevaccination), declined at 6 months (3.3-fold increase), and increased at 1 month postbooster (41.5-fold increase). Three months postbooster, IC50 decreased in coronavirus disease (COVID)-naïve individuals (18-fold increase) and increased in prior COVID 2019 (COVID-19+) individuals (132-fold increase). Age >65 years (β = −0.94, P = .001) and malignancy (β = −0.88, P = .002) reduced strength of response at 1 month. Both neutralization strength and durability at 6 months, respectively, were negatively affected by end-stage renal disease ([β = −1.10, P = .004]; [β = −0.66, P = .014]), diabetes mellitus ([β = −0.57, P = .032]; [β = −0.44, P = .028]), and systemic steroid use ([β = −0.066, P = .032]; [β = −0.55, P = .037]). Postbooster IC50 was robust against WA-1 and B.1.617.2. Postbooster neutralization increased with prior COVID-19 (β = 2.9, P < .0001), and malignancy reduced neutralization response (β = −0.68, P = .03), regardless of infection status. Conclusions Multiple clinical factors affect the strength and duration of neutralization response after primary series vaccination, but not the postbooster dose strength. Malignancy was associated with lower booster-dose response regardless of prior COVID infection, suggesting a need for clinically guided vaccine regimens. more...
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- 2022
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9. Infection by SARS-CoV-2 with alternate frequencies of mRNA vaccine boosting for patients undergoing antineoplastic treatment for cancer
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Jeffrey P. Townsend, Hayley Hassler, Brinda Emu, and Alex Dornburg
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Patients undergoing antineoplastic therapies often exhibit reduced immune response to COVID-19 vaccination, necessitating assessment of alternate boosting frequencies for these patients. However, data on reinfection risks to guide clinical decision-making is limited. We quantified reinfection risks of SARS-CoV-2 at different mRNA boosting frequencies of patients on antineoplastic therapies. Antibody levels following Pfizer-BioNTech BNT162b2 vaccination were analyzed for patients without cancer, with cancer undergoing various treatments, and treated with different antineoplastic therapeutics. Using long-term antibody data from other coronaviruses in an evolutionary framework, we estimated infection probabilities based on antibody levels and projected waning. We calculated cumulative probabilities of breakthrough infection for alternate booster schedules over two years. Annual boosting reduced risks for targeted or hormonal treatments, immunotherapy, and chemotherapy-immunotherapy combinations similarly to the general population. Patients receiving no treatment or chemotherapy exhibited higher risks, suggesting that accelerated vaccination schedules should be considered. Patients treated with rituximab therapy posed the highest infection risk, suggesting that a combination of frequent boosting and additional interventions may be warranted for mitigating SARS-CoV-2 infection in these patients. more...
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- 2023
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10. Safety and Activity of Immune Checkpoint Inhibitors in People Living With HIV and Cancer: A Real-World Report From the Cancer Therapy Using Checkpoint Inhibitors in People Living With HIV-International (CATCH-IT) Consortium
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Talal El Zarif, Amin H. Nassar, Elio Adib, Bailey G. Fitzgerald, Jiaming Huang, Tarek H. Mouhieddine, Paul G. Rubinstein, Taylor Nonato, Rana R. McKay, Mingjia Li, Arjun Mittra, Dwight H. Owen, Robert A. Baiocchi, Michael Lorentsen, Christopher Dittus, Nazli Dizman, Adewunmi Falohun, Noha Abdel-Wahab, Adi Diab, Anand Bankapur, Alexandra Reed, Chul Kim, Aakriti Arora, Neil J. Shah, Edward El-Am, Elie Kozaily, Wassim Abdallah, Ahmad Al-Hader, Batool Abu Ghazal, Anwaar Saeed, Claire Drolen, Melissa G. Lechner, Alexandra Drakaki, Javier Baena, Caroline A. Nebhan, Tarek Haykal, Michael A. Morse, Alessio Cortellini, David J. Pinato, Alessia Dalla Pria, Evan Hall, Veli Bakalov, Nathan Bahary, Aarthi Rajkumar, Ankit Mangla, Vishal Shah, Parminder Singh, Frank Aboubakar Nana, Nerea Lopetegui-Lia, Danai Dima, Ryan W. Dobbs, Pauline Funchain, Rabia Saleem, Rachel Woodford, Georgina V. Long, Alexander M. Menzies, Carlo Genova, Giulia Barletta, Sonam Puri, Vaia Florou, Dame Idossa, Maristella Saponara, Paola Queirolo, Giuseppe Lamberti, Alfredo Addeo, Melissa Bersanelli, Dory Freeman, Wanling Xie, Erin G. Reid, Elizabeth Y. Chiao, Elad Sharon, Douglas B. Johnson, Ramya Ramaswami, Mark Bower, Brinda Emu, Thomas U. Marron, Toni K. Choueiri, Lindsey R. Baden, Kathryn Lurain, Guru P. Sonpavde, and Abdul Rafeh Naqash more...
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Cancer Research ,Oncology - Abstract
PURPOSE Compared with people living without HIV (PWOH), people living with HIV (PWH) and cancer have traditionally been excluded from immune checkpoint inhibitor (ICI) trials. Furthermore, there is a paucity of real-world data on the use of ICIs in PWH and cancer. METHODS This retrospective study included PWH treated with anti–PD-1- or anti–PD-L1-based therapies for advanced cancers. Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS). Objective response rates (ORRs) were measured per RECIST 1.1 or other tumor-specific criteria, whenever feasible. Restricted mean survival time (RMST) was used to compare OS and PFS between matched PWH and PWOH with metastatic NSCLC (mNSCLC). RESULTS Among 390 PWH, median age was 58 years, 85% (n = 331) were males, 36% (n = 138) were Black; 70% (n = 274) received anti–PD-1/anti–PD-L1 monotherapy. Most common cancers were NSCLC (28%, n = 111), hepatocellular carcinoma ([HCC]; 11%, n = 44), and head and neck squamous cell carcinoma (HNSCC; 10%, n = 39). Seventy percent (152/216) had CD4+ T cell counts ≥200 cells/µL, and 94% (179/190) had HIV viral load CONCLUSION Among PWH, ICIs demonstrated differential activity across cancer types with no excess toxicity. Safety and activity of ICIs were similar between matched cohorts of PWH and PWOH with mNSCLC. more...
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- 2023
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11. Building an Infectious Disease Diversity, Equity, and Antiracism (ID2EA) Curriculum: A Single Center’s Experience and Reflections
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Shana E Gleeson, Heidi Zapata, Meghan E Bathgate, Brinda Emu, Jennifer Frederick, Gerald Friedland, Marjorie P Golden, Jaimie P Meyer, Joanna Radin, Robert Sideleau, Albert Shaw, Sheela V Shenoi, Paul A Trubin, Michael Virata, Lydia A Barakat, and Mahalia S Desruisseaux more...
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Microbiology (medical) ,Infectious Diseases - Abstract
In response to longstanding healthcare inequities unmasked by the COVID-19 pandemic, the Infectious Diseases Section at the Yale School of Medicine designed and implemented a pilot curriculum integrating Diversity, Equity, and Anti-racism (ID2EA) into Infectious Disease educational training and measured program outcomes. We herein describe a mixed-methods assessment of Section members on whether the ID2EA curriculum impacted their beliefs and behaviors regarding racism and healthcare inequities. Participants rated the curriculum as useful (92% averaging across sessions) and effective in achieving stated learning objectives (89% averaging across sessions), including fostering understanding of how inequities and racism are linked to health disparities and identifying strategies to effectively deal with racism and inequities. Despite limitations in response rates and assessment of longer-term behavioral change, this work demonstrates that training in diversity, equity, and anti-racism can be successfully integrated into Infectious Disease physicians’ educational activities and impact physicians’ perspectives on these topics. more...
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- 2023
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12. Cancer Microbiology
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Daniel DiMaio, Brinda Emu, Andrew L Goodman, Walther Mothes, and Amy Justice
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Cancer Research ,Oncology ,Microbiota ,Neoplasms ,Carcinogens ,Reviews ,Humans ,Delivery of Health Care ,Anti-Bacterial Agents - Abstract
Microbes play important roles in cancer from direct carcinogenic effects to their use in treatment. Cancers caused by microorganisms account for approximately 15% of cancers, primarily in low- and middle-income countries. Unique features of infectious carcinogens include their transmissibility, mutability, and specific immune interactions, which provide challenges and opportunities for cancer prevention and treatment. For these agents, infection control through exposure reduction, antivirals, antibiotics, and vaccines is cancer control. In addition, developing evidence suggests that microorganisms including the human microbiome can indirectly modulate cancer formation and influence the effectiveness and toxicity of cancer treatments. Finally, microorganisms themselves can be used to prevent or treat cancer. The convergence of these factors signals the emergence of a new field, cancer microbiology. Recognition of cancer microbiology will spur research, stimulate cross-disciplinary training, inform drug development, and improve public health. more...
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- 2021
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13. 437 Safety and efficacy of immune checkpoint inhibitors (ICI) in patients living with HIV (PLWH) and metastatic non-small cell lung cancer (NSCLC): a matched cohort study from the international CATCH-IT consortium
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Talal El Zarif, Amin Nassar, Elio Adib, Bailey Fitzgerald, Jiaming Huang, Tarek Mouhieddine, Taylor Nonato, Rana McKay, Mingjia Li, Arjun Mittra, Dwight Owen, Michael Lorentsen, Christopher Dittus, Nazli Dizman, Brinda Emu, Adewunmi Falohun, Noha Abdel-Wahab, Anand Bankapur, Alexandra Reed, Ryan Dobbs, Chul Kim, Aakriti Arora, Neil Shah, Edward El-Am, Elie Kozaily, Wassim Abdallah, Ahmad Al-Hader, Batool Abu Ghazal, Anwaar Saeed, Claire Drolen, Melissa Lechner, Javier Espinar, Caroline Nebhan, Douglas Johnson, Tarek Haykal, Michael Morse, Alessio Cortellini, David Pinato, Alessia Dalla Pria, Mark Bower, Evan Hall, Veli Bakalov, Nathan Bahary, Aarthi Rajkumar, Ankit Mangla, Vishal Shah, Parminder Singh, Frank Aboubakar Nana, Nerea Lopetegui Lia, Danai Dima, Pauline Funchain, Rabia Saleem, Rachel Woodford, Georgina Long AO, Alexander Menzies, Carlo Genova, Giulia Barletta, Sonam Puri, Vaia Florou, Dame Idossa, Paola Queirolo, Giuseppe Lamberti, Alfredo Addeo, Melissa Bersanelli, Dory Freeman, Wanling Xie, Ramya Ramaswami, Thomas Marron, Toni Choueiri, Kathryn Lurain, Lindsey Baden, Guru Sonpavde, and Abdul Rafeh Naqash more...
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- 2022
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14. Alterations in high‐dimensional T‐cell profile and gene signature of immune aging in <scp>HIV</scp> ‐infected older adults without viremia
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Min Sun Shin, Hong‐Jai Park, Syim Salahuddin, Ruth R. Montgomery, Brinda Emu, Albert C. Shaw, and Insoo Kang
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CD4-Positive T-Lymphocytes ,Aging ,Receptors, Interleukin-7 ,Perforin ,Leukocytes, Mononuclear ,Humans ,HIV Infections ,Viremia ,Cell Biology ,CD8-Positive T-Lymphocytes ,Aged - Abstract
Alterations in the components of the immune system occur with aging. The introduction of combination antiretroviral therapy (ART) has dramatically improved life expectancy in human immunodeficiency virus (HIV) infected individuals by suppressing viral replication and increasing CD4 more...
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- 2022
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15. HIV is associated with poor overall survival among head and neck cancer patients
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Syim, Salahuddin, Oded, Cohen, Margaret, Wu, Javier, Perez Irizarry, Teresita, Vega, Geliang, Gan, Yanhong, Deng, Natalia, Isaeva, Manju, Prasad, Kurt A, Schalper, Saral, Mehra, Wendell G, Yarbrough, and Brinda, Emu more...
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Head and neck squamous cell cancer (HNC) occurs at higher rates among people with HIV (PWH). This study compares the impact of sociodemographic and clinicopathologic characteristics on outcomes among PWH-HNSCC compared to Uninfected- HNSCC patients.Patient data from individuals with HNSCC were collected at a single academic hospital center between 2002 and 2018. 48 patients with HIV infection (HIV-HNSCC) and 2894 uninfected patients (Uninfected-HNSCC) were included. Multivariate analysis determined predictors of survival using Cox proportional hazards regression model. HIV + and HIV- tumors were analyzed by quantitative immunofluorescence for expression of CD4, CD8, CD20 and PD-L1.HIV-HNSCC patients had lower median overall survival compared to Uninfected-HNSCC patients (34 [18-84] vs. 94 [86-103] months, p 0.001). In a multivariate analysis that included age, sex, race/ethnicity, stage, site, tobacco use, time to treatment initiation, and insurance status, HIV infection was an independent predictor of poorer survival with a hazard ratio of 1.98 (95% CI 1.32-2.97, p 0.001). PWH with HPV + oropharyngeal tumors also had worse prognosis compared to HPV + oropharyngeal tumors in the HIV-Uninfected population(p 0.001). The tumor microenvironment among HIV-HNSCC patients revealed lower intra-tumoral CD8 infiltration among HIV + HPV + tumors compared to HIV-HPV + tumors (p = 0.04).HNSCC patients with HIV had worse prognosis compared to the general population, with HIV being an independent predictor of poor clinical outcomes when accounting for important sociodemographic and clinicopathologic factors. Our findings highlight differences in tumor biology that require further detailed characterization in large cohorts and increased inclusion of PWH in immunotherapy trials. more...
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- 2022
16. Correlation between CD4/CD8 ratio and neurocognitive performance during early HIV infection
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Leah T. Le, Richard W. Price, Magnus Gisslén, Henrik Zetterberg, Brinda Emu, Roxane Fabre, Pradier Christian, Signe Andersen, Serena Spudich, and Matteo Vassallo
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Infectious Diseases ,Health Policy ,Pharmacology (medical) - Abstract
CD4/CD8 ratio is a marker of immune activation in HIV infection and has been associated with neurocognitive performance during chronic infection, but little is known about the early phases. The aim of this study was to examine the relationship between blood CD4/CD8 ratio and central nervous system endpoints in primary HIV infection (PHI) before and after antiretroviral treatment (ART).This was a retrospective analysis of the Primary Infection Stage CNS Events Study (PISCES) cohort. We longitudinally assessed blood and cerebrospinal fluid (CSF) markers of inflammation, immune activation and neuronal injury, and neuropsychological testing performance (NPZ4, an average of three motor and one processing speed tests, and a summarized total score, NPZ11, including also executive function, learning and memory) in ART-naïve participants enrolled during PHI. Spearman correlation and linear mixed models assessed the relationships between the trajectory of CD4/CD8 ratio over time and neurocognitive performance, blood and CSF markers of immune activation and neuronal injury.In all, 109 PHI participants were enrolled. The mean CD4/CD8 ratio decreased with longer time from infection to starting treatment (p 0.001). Every unit increase in NPZ4 score was independently associated with a 0.15 increase in CD4/CD8 ratio (95% CI: 0.002-0.29; p = 0.047), whereas no correlation was found between CD4/CD8 ratio and NPZ11. Among the cognitive domains, only a change in processing speed was correlated with CD4/CD8 ratio over time (p = 0.03). The trajectory of the CD4/CD8 ratio was negatively correlated with change in CSF neurofilament light chain (p = 0.04).The trajectory of CD4/CD8 ratio was independently associated with motor/psychomotor speed performance, suggesting that immune activation is involved in brain injury during the early stages of the infection. more...
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- 2022
17. Clinical Variables Correlate with Serum Neutralizing Antibody Titers after COVID-19 mRNA Vaccination in an Adult, US-based Population
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Min Zhao, Rebecca Slotkin, Amar H. Sheth, Lauren Pischel, Tassos C. Kyriakides, Brinda Emu, Cynthia McNamara, Qiaosu Shi, Jaden Delgobbo, Jin Xu, Elizabeth Marhoffer, Aleagia Mercer-Falkoff, Jürgen Holleck, David Ardito, Richard E. Sutton, and Shaili Gupta more...
- Abstract
BackgroundWe studied whether comorbid conditions impact strength and duration of immune responses after SARS-CoV-2 mRNA vaccination in a US-based, adult population.MethodsSera (pre-and-post-BNT162b2 vaccination) were tested serially up to 12 months after two doses of vaccine for SARS-CoV-2-anti-Spike neutralizing capacity by pseudotyping assay in 124 individuals; neutralizing titers were correlated to clinical variables with multivariate regression. Post-booster (third dose) effect was measured at 1 and 3 months in 72 and 88 subjects respectively.ResultsAfter completion of primary vaccine series, neutralizing antibody IC50 values were high at one month (14-fold increase from pre-vaccination), declined at six months (3.3-fold increase), and increased at one month post-booster (41.5-fold increase). Three months post-booster, IC50 decreased in COVID-naïve individuals (18-fold increase) and increased in prior COVID-19+ individuals (132-fold increase). Age >65 years (β=-0.94, p=0.001) and malignancy (β=-0.88, p=0.002) reduced strength of response at 1 month. Both strength and durability of response at 6 months, respectively, were negatively impacted by end-stage renal disease [(β=-1.10, p=0.004); (β=-0.66, p=0.014)], diabetes mellitus [(β=-0.57, p=0.032); (β=-0.44, p=0.028)], and systemic steroid use [(β=-0.066, p=0.032); (β=-0.55, p=0.037)]. Post-booster IC50 was robust against WA-1 and B.1.617.2, but the immune response decreased with malignancy (β =-0.68, p=0.03) and increased with prior COVID-19 (p-value < 0.0001).ConclusionMultiple clinical factors impact the strength and duration of neutralization response post-primary series vaccination, but not the post-booster dose strength. Prior COVID-19 infection enhances the booster-dose response except in individuals with malignancy, suggesting a need for clinically guiding vaccine dosing regimens.SummaryMultiple clinical factors impact the strength and duration of neutralization response post-primary series vaccination. All subjects, irrespective of prior COVID infection, benefited from a third dose. Malignancy decreased response following third dose, suggesting the importance of clinically guided vaccine regimens. more...
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- 2022
18. Opening the door on entry inhibitors in HIV: Redefining the use of entry inhibitors in heavily treatment experienced and treatment-limited individuals living with HIV
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Chloe Orkin, Pedro Cahn, Antonella Castagna, Brinda Emu, P Richard Harrigan, Daniel R. Kuritzkes, Mark Nelson, and Jonathan Schapiro
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Infectious Diseases ,Anti-HIV Agents ,Health Policy ,Drug Resistance, Viral ,HIV-1 ,Humans ,Pharmacology (medical) ,HIV Infections - Abstract
Entry inhibitors are a relatively new class of antiretroviral therapy and are typically indicated in heavily treatment experienced individuals living with HIV. Despite this, there is no formal definition of 'heavily treatment experienced'. Interpretation of this term generally includes acknowledgement of multidrug resistance and reflects the fact that patients in need of further treatment options may have experienced multiple lines of therapy. However, it fails to recognize treatment limiting factors including contraindications, age-associated comorbidities, and difficulty adhering to regimens.This manuscript follows a roundtable discussion and aims to identify the unmet needs of those living with HIV who are in need of further treatment options, to broaden the definition of heavily treatment experienced and to clarify the use of newer agents, with an emphasis on the potential role of entry inhibitors, in this population.Within the entry inhibitor class, mechanisms of action differ between agents; resistance to one subclass does not confer resistance to others. Combinations of entry inhibitors should be considered in the same regimen, and if lack of response is seen to one entry inhibitor another can be tried. When selecting an entry inhibitor, physicians should account for patient preferences and needs as well as agent-specific clinical characteristics. Absence of documented multidrug resistance should not exclude an individual from treatment with an entry inhibitor; entry inhibitors are a valuable treatment option for all individuals who are treatment limited or treatment exhausted. We should advocate for additional clinical trials that help define the role of entry inhibitors in people with exhausted/limited ART options other than drug resistance. more...
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- 2022
19. Serum Neutralizing Antibody Titers 12 months after COVID-19 mRNA Vaccination: Correlation to Clinical Variables in an Adult, US-Population
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Min, Zhao, Rebecca, Slotkin, Amar H, Sheth, Lauren, Pischel, Tassos C, Kyriakides, Brinda, Emu, Cynthia, McNamara, Qiaosu, Shi, Jaden, Delgobbo, Jin, Xu, Elizabeth, Marhoffer, Aleagia, Mercer-Falkoff, Jürgen, Holleck, David, Ardito, Richard E, Sutton, and Shaili, Gupta more...
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Article - Abstract
We studied whether comorbid conditions impact strength and duration of immune responses after SARS-CoV-2 mRNA vaccination in a US-based, adult population.Sera (pre-and-post-BNT162b2 vaccination) were tested serially up to 12 months after two doses of vaccine for SARS-CoV-2-anti-Spike neutralizing capacity by pseudotyping assay in 124 individuals; neutralizing titers were correlated to clinical variables with multivariate regression. Post-booster (third dose) effect was measured at 1 and 3 months in 72 and 88 subjects respectively.After completion of primary vaccine series, neutralizing antibody IC50 values were high at one month (14-fold increase from pre-vaccination), declined at six months (3.3-fold increase), and increased at one month post-booster (41.5-fold increase). Three months post-booster, IC50 decreased in COVID-naïve individuals (18-fold increase) and increased in prior COVID-19 + individuals (132-fold increase). Age65 years (β=-0.94, p = 0.001) and malignancy (β=-0.88, p = 0.002) reduced strength of response at 1 month. Both neutralization strength and durability at 6 months, respectively, were negatively impacted by end-stage renal disease [(β=-1.10, p = 0.004); (β=-0.66, p = 0.014)], diabetes mellitus [(β=-0.57, p = 0.032); (β=-0.44, p = 0.028)], and systemic steroid use [(β=-0.066, p = 0.032); (β=-0.55, p = 0.037)]. Post-booster IC50 was robust against WA-1 and B.1.617.2. Post-booster neutralization increased with prior COVID-19 (β = 2.9, p-value0.0001), and malignancy reduced neutralization response (β=-0.68, p = 0.03), regardless of infection status.Multiple clinical factors impact the strength and duration of neutralization response post-primary series vaccination, but not the post-booster dose strength. Malignancy was associated with lower booster-dose response regardless of prior COVID infection, suggesting a need for clinically guided vaccine regimens. more...
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- 2022
20. PD-1highCXCR5–CD4+ peripheral helper T cells promote CXCR3+ plasmablasts in human acute viral infection
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Hiromitsu Asashima, Subhasis Mohanty, Michela Comi, William E. Ruff, Kenneth B. Hoehn, Patrick Wong, Jon Klein, Carolina Lucas, Inessa Cohen, Sarah Coffey, Nikhil Lele, Leissa Greta, Khadir Raddassi, Omkar Chaudhary, Avraham Unterman, Brinda Emu, Steven H. Kleinstein, Ruth R. Montgomery, Akiko Iwasaki, Charles S. Dela Cruz, Naftali Kaminski, Albert C. Shaw, David A. Hafler, and Tomokazu S. Sumida more...
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General Biochemistry, Genetics and Molecular Biology - Published
- 2023
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21. PD-1
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Hiromitsu, Asashima, Subhasis, Mohanty, Michela, Comi, William E, Ruff, Kenneth B, Hoehn, Patrick, Wong, Jon, Klein, Carolina, Lucas, Inessa, Cohen, Sarah, Coffey, Nikhil, Lele, Leissa, Greta, Khadir, Raddassi, Omkar, Chaudhary, Avraham, Unterman, Brinda, Emu, Steven H, Kleinstein, Ruth R, Montgomery, Akiko, Iwasaki, Charles S, Dela Cruz, Naftali, Kaminski, Albert C, Shaw, David A, Hafler, and Tomokazu S, Sumida more...
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T cell-B cell interaction is the key immune response to protect the host from severe viral infection. However, how T cells support B cells to exert protective humoral immunity in humans is not well understood. Here, we use COVID-19 as a model of acute viral infections and analyze CD4 more...
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- 2021
22. Abstract 418: Lower survival among HIV-infected head and neck cancer patients
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Syim Salahuddin, Kurt A. Schalper, Wendell G. Yarbrough, Margaret Wu, Teresita Vega, Natalia Isaeva, Brinda Emu, and Javier Perez Irizarry
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Oncology ,education.field_of_study ,medicine.medical_specialty ,Quantitative immunofluorescence ,business.industry ,Incidence (epidemiology) ,Population ,Head and neck cancer ,Cancer ,medicine.disease ,Tumor site ,Tumor registry ,Internal medicine ,Hiv infected ,medicine ,education ,business - Abstract
Introduction: Incidence of non-AIDS-defining cancers, including head and neck cancer (HNC), is rising among people living with HIV (PLWH). This study compares outcomes of HIV+ and Uninfected HNC patients at a single institution. Methods: Yale Tumor Registry query identified 3,488 HNC patients, including 50 with HIV, for analysis (Clinical Cohort, 2002-2018). Quantitative immunofluorescence (QIF) was performed on tumor tissue among 22 HIV+ and 75 matched Uninfected patients. Results: Within our clinical cohort, HIV+ HNC patients were younger compared to Uninfected patients (55.5 vs. 62.0, p Conclusion: HNC patients with HIV were significantly younger compared to the general HNC population, and experienced lower 1-yr survival with early stage disease. CD8 T cell infiltration, which is associated with improved outcomes, appears lower among PLWH. Further evaluation of HIV-HNC subgroups, with detailed analysis of tumor site, HPV status and treatment disparities, is warranted to better delineate differences in outcome. Citation Format: Syim Salahuddin, Margaret Wu, Javier Perez Irizarry, Teresita Vega, Natalia Isaeva, Kurt Schalper, Wendell G. Yarbrough, Brinda Emu. Lower survival among HIV-infected head and neck cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 418. more...
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- 2021
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23. Palliation of malignancies in HIV infection
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Faiza Yasin, Ronald Chow, Elizabeth Horn Prsic, Brinda Emu, and Trinh Bui
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medicine.medical_specialty ,medicine.drug_class ,Nausea ,medicine.medical_treatment ,Antibiotics ,Medicine (miscellaneous) ,Integrase inhibitor ,030204 cardiovascular system & hematology ,Nucleoside Reverse Transcriptase Inhibitor ,03 medical and health sciences ,0302 clinical medicine ,Acquired immunodeficiency syndrome (AIDS) ,Internal medicine ,medicine ,030212 general & internal medicine ,Chemotherapy ,Oncology (nursing) ,business.industry ,virus diseases ,Cancer ,General Medicine ,medicine.disease ,Medical–Surgical Nursing ,Vomiting ,medicine.symptom ,business - Abstract
It is important to consider medication interactions and overlapping medication toxicities in persons living with HIV (PLWH) who are on combination antiretroviral therapy (cART), in addition to disease-specific cancer therapy, medications to alleviate cytotoxic effects of chemotherapy, prophylaxis to prevent infection or medications for palliation. Protease inhibitors, integrase inhibitors, nucleoside reverse transcriptase inhibitors (NRTIs) and non-NRTIs are the major components of commonly used cART regimens, and are metabolised via the cytochrome P450 (CYP450) system of the liver. Many antineoplastic agents, and supportive therapies, including those medications required for management of opportunistic infections (anti-infective medications including antifungal agents and antibiotics), nausea/vomiting (antiemetics and steroids), cancer-related pain (opioid analgesics) and comorbid psychiatric disorders (selective-serotonin … more...
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- 2021
24. NASH limits anti-tumour surveillance in immunotherapy-treated HCC
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Stephan Spahn, Florian Müller, Revant Gupta, Dominik Pfister, Kornelius Schulze, Pierre Bedossa, Eleni Kotsiliti, Lars Zender, Mathias Heikenwalder, Nicolás Gonzalo Núñez, Peter Schirmacher, Axel Schulz, Jan Kosla, Adrian T. Billeter, Thomas Engleitner, Aleksandra Deczkowska, Danijela Heide, Donato Inverso, Susanne Roth, Olivier Govaere, Carla Montironi, Martha M. Kirstein, Dan G. Duda, Antonio D'Alessio, Jörn M. Schattenberg, Ekaterina Friebel, Tiziana Pressiani, F. Hucke, Jörg Trojan, Michael Bitzer, Suhail Yousuf, Bernhard Scheiner, Marina Ruiz de Galarreta, Markus Peck-Radosavljevic, Michael Allison, Nuh N. Rahbari, Simon Cockell, Brinda Emu, Ahmed Kaseb, David J. Pinato, Matthias P. Ebert, Joachim C. Mertens, Jean-François Dufour, Fabian Rössler, Achim Weber, Katharina Wolter, Thomas Decaens, Amaia Lujambio, Anja Moncsek, Daniela Lenggenhager, Katharina Pomej, Nisar P. Malek, Fabian Finkelmeier, Elisabetta Bugianesi, Valentina Leone, Ann K. Daly, Michael Dudek, Manfred Claassen, Zuzana Macek Jilkova, Henning Wege, Florian Castet, Marta Szydlowska, Beat P. Müller-Stich, Ramy Younes, Nicola Personeni, Philipp K. Haber, Marco Bueter, Manfred Jugold, Andrea Schietinger, Hiroto Kikuchi, Ido Amit, Sandra Koch, Dina Tiniakos, Ana Teijeiro, Jan-Philipp Mallm, Josep M. Llovet, Indrabahadur Singh, Percy A. Knolle, Sara De Dosso, Roland Rad, Arndt Vogel, Henrik E. Mei, Burkhard Becher, Nabil Djouder, Tom Luedde, Felix Meissner, Oliver Waidmann, Parice N. Marche, Viktor Umansky, Hellmut G. Augustin, Thomas U. Marron, Matthias Pinter, Mengjie Qiu, Arndt Weinmann, Ankit Sinha, Kristian Unger, Assaf Weiner, Vlad Ratziu, Quentin M. Anstee, Kristin Stirm, Yi Hsiang Huang, Alexander Siebenhüner, Fabian Kütting, Lorenza Rimassa, Dirk Waldschmidt, Masatoshi Kudo, Marc Ringelhan, Michele Vacca, Roser Pinyol, Fabio Marra, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Novo Nordisk A/S [Maløv, Denmark], Universität Zürich [Zürich] = University of Zurich (UZH), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), Newcastle University [Newcastle], Medizinische Universität Wien = Medical University of Vienna, University of Tübingen, UniversitätsKlinikum Heidelberg, Weizmann Institute of Science [Rehovot, Israël], Max Planck Institute of Biochemistry (MPIB), Max-Planck-Gesellschaft, Technical University of Munich (TUM), University hospital of Zurich [Zurich], Helmholtz-Zentrum München (HZM), Heidelberg University, Spanish National Cancer Research Center (CNIO), Icahn School of Medicine at Mount Sinai [New York] (MSSM), National and Kapodistrian University of Athens (NKUA), University of Turin, Addenbrooke's Hospital, Cambridge University NHS Trust, Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), University Medical Center [Mainz], Cambridge University Hospitals - NHS (CUH), University of Cambridge [UK] (CAM), Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Diderot - Paris 7 (UPD7), Istituto Clinico Humanitas [Milan] (IRCCS Milan), Humanitas University [Milan] (Hunimed), Hannover Medical School [Hannover] (MHH), University Medical Center of Schleswig–Holstein = Universitätsklinikum Schleswig-Holstein (UKSH), Kiel University, Klinikum Klagenfurt am Wörthersee, Universitätsklinikum Frankfurt, Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Oncology Institute of Southern Switzerland (IOSI), Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], Memorial Sloane Kettering Cancer Center [New York], Weill Medical College of Cornell University [New York], Heidelberg University Hospital [Heidelberg], Medical Faculty [Mannheim], Massachusetts General Hospital [Boston], University of Cologne, Deutsches Rheuma-ForschungsZentrum (DRFZ), Deutsches Rheuma-ForschungsZentrum, German Center for Infection Research, Partnersite Munich (DZIF), University Medical Center [Tubingen, Germany], Inselspital Bern, University of Bern, The University of Texas M.D. Anderson Cancer Center [Houston], Kindai University, National Yang Ming University (NYMU), Taipei Veterans General Hospital [Taiwan], Universitätsklinikum Tübingen - University Hospital of Tübingen, Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Eberhard Karls University [Tübingen, Germany], Université Grenoble Alpes (UGA), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), CHU Grenoble, Hammersmith Hospital NHS Imperial College Healthcare, Università degli Studi del Piemonte Orientale - Amedeo Avogadro (UPO), Institució Catalana de Recerca i Estudis Avançats (ICREA), Pfister, Dominik [0000-0002-0542-2638], Núñez, Nicolás Gonzalo [0000-0003-3837-270X], Govaere, Olivier [0000-0002-4426-6930], Szydlowska, Marta [0000-0002-4660-899X], Gupta, Revant [0000-0002-0881-5074], Deczkowska, Aleksandra [0000-0003-0844-4346], Friebel, Ekaterina [0000-0003-1419-2376], Lenggenhager, Daniela [0000-0002-5382-9854], Moncsek, Anja [0000-0002-1191-5842], Inverso, Donato [0000-0003-0987-3345], Vacca, Michele [0000-0002-1973-224X], Marra, Fabio [0000-0001-8629-0878], Allison, Michael [0000-0003-3677-3294], D'Alessio, Antonio [0000-0002-9164-3671], Personeni, Nicola [0000-0002-7995-272X], Rimassa, Lorenza [0000-0001-9957-3615], Pomej, Katharina [0000-0002-2807-3565], Peck-Radosavljevic, Markus [0000-0002-0597-2728], Mallm, Jan-Philipp [0000-0002-7059-4030], Schietinger, Andrea [0000-0003-3644-1687], Augustin, Hellmut G [0000-0002-7173-4242], Kikuchi, Hiroto [0000-0002-3601-8435], Duda, Dan G [0000-0001-7065-8797], Mei, Henrik E [0000-0003-0697-7755], Schulz, Axel Ronald [0000-0002-5106-0148], Ringelhan, Marc [0000-0003-3131-5657], Lujambio, Amaia [0000-0002-2798-1481], Dufour, Jean-Francois [0000-0002-8062-1346], Kudo, Masatoshi [0000-0002-4102-3474], Djouder, Nabil [0000-0001-8423-1030], Zender, Lars [0000-0001-7626-2849], Pinato, David J [0000-0002-3529-0103], Rad, Roland [0000-0002-6849-9659], Mertens, Joachim C [0000-0003-2007-0308], Weber, Achim [0000-0003-0073-3637], Meissner, Felix [0000-0003-1000-7989], Amit, Ido [0000-0003-2968-877X], Knolle, Percy [0000-0003-2983-0414], Becher, Burkhard [0000-0002-1541-7867], Llovet, Josep M [0000-0003-0547-2667], Heikenwalder, Mathias [0000-0002-3135-2274], Apollo - University of Cambridge Repository, Max-Planck-Institut für Biochemie = Max Planck Institute of Biochemistry (MPIB), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Helmholtz Zentrum München = German Research Center for Environmental Health, Università degli studi di Torino = University of Turin (UNITO), Università degli Studi di Firenze = University of Florence (UniFI), MARCHE, Patrice, D’Alessio, Antonio [0000-0002-9164-3671], Augustin, Hellmut G. [0000-0002-7173-4242], Duda, Dan G. [0000-0001-7065-8797], Mei, Henrik E. [0000-0003-0697-7755], Pinato, David J. [0000-0002-3529-0103], Mertens, Joachim C. [0000-0003-2007-0308], and Llovet, Josep M. [0000-0003-0547-2667] more...
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Male ,Carcinogenesis ,medicine.medical_treatment ,[SDV]Life Sciences [q-bio] ,Programmed Cell Death 1 Receptor ,CD8-Positive T-Lymphocytes ,B7-H1 Antigen ,13/2 ,13/1 ,Mice ,0302 clinical medicine ,Non-alcoholic Fatty Liver Disease ,LIVER-CANCER ,R PACKAGE ,RNA-SEQ ,14/19 ,Cancer ,0303 health sciences ,Multidisciplinary ,NONALCOHOLIC STEATOHEPATITIS ,Liver Neoplasms ,article ,ddc ,3. Good health ,13/31 ,Multidisciplinary Sciences ,medicine.anatomical_structure ,Liver ,030220 oncology & carcinogenesis ,Hepatocellular carcinoma ,Disease Progression ,Science & Technology - Other Topics ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,64/60 ,Tumor necrosis factor alpha ,Immunotherapy ,Adjuvant ,631/67 ,Carcinoma, Hepatocellular ,[SDV.IMM] Life Sciences [q-bio]/Immunology ,T cell ,610 Medicine & health ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,14/32 ,03 medical and health sciences ,14/34 ,13/21 ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,ADVANCED HEPATOCELLULAR-CARCINOMA ,NAFLD ,medicine ,Animals ,Humans ,14/35 ,030304 developmental biology ,Science & Technology ,Tumor Necrosis Factor-alpha ,business.industry ,631/250/251 ,medicine.disease ,PHASE-III ,digestive system diseases ,13/51 ,14/63 ,59/57 ,T-CELLS ,Cancer research ,Steatohepatitis ,business ,CD8 - Abstract
Hepatocellular carcinoma (HCC) can have viral or non-viral causes1–5. Non-alcoholic steatohepatitis (NASH) is an important driver of HCC. Immunotherapy has been approved for treating HCC, but biomarker-based stratification of patients for optimal response to therapy is an unmet need6,7. Here we report the progressive accumulation of exhausted, unconventionally activated CD8+PD1+ T cells in NASH-affected livers. In preclinical models of NASH-induced HCC, therapeutic immunotherapy targeted at programmed death-1 (PD1) expanded activated CD8+PD1+ T cells within tumours but did not lead to tumour regression, which indicates that tumour immune surveillance was impaired. When given prophylactically, anti-PD1 treatment led to an increase in the incidence of NASH–HCC and in the number and size of tumour nodules, which correlated with increased hepatic CD8+PD1+CXCR6+, TOX+, and TNF+ T cells. The increase in HCC triggered by anti-PD1 treatment was prevented by depletion of CD8+ T cells or TNF neutralization, suggesting that CD8+ T cells help to induce NASH–HCC, rather than invigorating or executing immune surveillance. We found similar phenotypic and functional profiles in hepatic CD8+PD1+ T cells from humans with NAFLD or NASH. A meta-analysis of three randomized phase III clinical trials that tested inhibitors of PDL1 (programmed death-ligand 1) or PD1 in more than 1,600 patients with advanced HCC revealed that immune therapy did not improve survival in patients with non-viral HCC. In two additional cohorts, patients with NASH-driven HCC who received anti-PD1 or anti-PDL1 treatment showed reduced overall survival compared to patients with other aetiologies. Collectively, these data show that non-viral HCC, and particularly NASH–HCC, might be less responsive to immunotherapy, probably owing to NASH-related aberrant T cell activation causing tissue damage that leads to impaired immune surveillance. Our data provide a rationale for stratification of patients with HCC according to underlying aetiology in studies of immunotherapy as a primary or adjuvant treatment., In hepatocellular carcinoma driven by non-alcoholic steatohepatitis, aberrant T cell activation and impaired immune surveillance seem to make hepatocellular carcinoma less responsive to anti-PD1 or anti-PDL1 immunotherapy. more...
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- 2021
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25. PD-1highCXCR5–CD4+ Peripheral Helper T (Tph) cells Promote Tissue-Homing Plasmablasts in COVID-19
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William Ruff, Brinda Emu, Ruth R. Montgomery, Tomokazu Sumida, Albert C. Shaw, Akiko Iwasaki, Inessa Cohen, Charles S. Dela Cruz, Subhasis Mohanty, David A. Hafler, Avraham Unterman, Omkar Chaudhary, Kenneth B. Hoehn, Sarah Coffey, Michela Comi, Naftali Kaminski, Khadir Raddassi, Steven H. Kleinstein, Hiromitsu Asashima, and Patrick Wong more...
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biology ,Chemistry ,CXCR3 ,Chemokine receptor ,medicine.anatomical_structure ,Immune system ,Immunity ,Immunology ,biology.protein ,medicine ,Antibody ,Receptor ,B cell ,Homing (hematopoietic) - Abstract
SummaryA dysregulated immune response against coronavirus-2 (SARS-CoV-2) plays a critical role in the outcome of patients with coronavirus disease 2019 (COVID-19). A significant increase in circulating plasmablasts is characteristic of COVID-19 though the underlying mechanisms and its prognostic implications are not known. Here, we demonstrate that in the acute phase of COVID-19, activated PD-1highCXCR5−CD4+ T cells, peripheral helper T cells, (Tph) are significantly increased and promote inflammatory tissue-homing plasmablasts in patients with stable but not severe COVID-19. Analysis of scRNA-seq data revealed that plasmablasts in stable patients express higher levels of tissue-homing receptors including CXCR3. The increased Tph cells exhibited “B cell help” signatures similar to that of circulating T follicular helper (cTfh) cells and promoted B cell differentiation in vitro. Compared with cTfh cells, Tph cells produced more IFNγ, inducing tissue-homing chemokine receptors on plasmablasts. Finally, expansion of activated Tph cells was correlated with the frequency of CXCR3+ plasmablasts in the acute phase of patients with stable disease. Our results demonstrate a novel role for Tph cells in acute viral immunity by inducing ectopic, antibody secreting plasmablasts. more...
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- 2021
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26. Impact of HIV infection on clinical outcomes among people diagnosed with head and neck cancer
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Syim Salahuddin, Oded Cohen, Margaret Wu, Javier Perez Irizarry, Teresita Vega, Geliang Gan, Yanhong Deng, Natalia Isaeva, Kurt A. Schalper, Saral Mehra, Wendell Gray Yarbrough, and Brinda Emu
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Cancer Research ,Oncology - Abstract
e18080 Background: Incidence of non-AIDS-defining cancers, including head and neck cancer (HNC), is rising among people with HIV (PWH) in the combination antiretroviral therapy (cART) era. The following study compares demographics, clinical outcomes, and the tumor microenvironment of HIV+ and Uninfected HNC patients at a single institution. Methods: Yale Tumor Registry query identified 3,356 HNC patients from 2002 to 2018 for analysis, including 50 PWH. In addition, quantitative immunofluorescence (QIF) was performed on tumor tissue from 22 PWH and 75 matched Uninfected patients. HPV status was based on p16 staining done universally among oropharyngeal squamous cell carcinomas (OPSCC) after 2010. Results: PWH were younger at cancer presentation compared to Uninfected patients (55.5 vs. 62.0, p < 0.001), with differences in race/ethnicity and insurance status (p < 0.001 for both). Biologic sex, tobacco use, alcohol consumption, anatomic site, stage at presentation, stage-specific treatment, and time to initiation of treatment were comparable between HIV+ and Uninfected cohorts. 89% of the PWH were on cART, with 79% achieving viral loads ≤200 copies/mL and a median CD4 count of 341 cells/mm³. Median survival among PWH was 39.1 months, compared to 100.8 months among Uninfected patients (p < 0.001). In a multivariate (MV) analysis that included age, sex, race/ethnicity, tobacco use, anatomic site, stage, time to treatment initiation and insurance status, HIV was an independent predictor of poor outcome (HR 1.88 with 95% CI: 1.25-2.81). Difference in survival was noted particularly in early stage (stages 0, I, II) cancer, with a median survival of 73.8 months in PWH compared to 141.9 months in Uninfected patients (p = 0.001). Survival was comparable among late stage (stages III, IV) HNC patients. Among PWH, increased HIV viral load was associated with poor outcome in a MV analysis (p = 0.03). Among HPV-associated OPSCC, PWH had decreased survival compared to Uninfected patients (p < 0.001). In our study of the tumor microenvironment by QIF, tumors of PWH had lower tumoral CD8 T cell infiltration (p = 0.04) and lower PD-L1 expression in tumor, stroma, and combined compartments (CPS) (p = 0.01, p = 0.03, and p = 0.01, respectively) compared to Uninfected patients. Conclusions: In our single institution study, HNC patients living with HIV experienced decreased overall survival, with HIV serving as an independent predictor of poor outcome in a multivariate analysis which included insurance status and treatment approaches. Difference in outcome was significant among early stage tumors and among HPV+ OPSCC. CD8 T cell infiltration and PD-L1 expression, both associated with improved outcomes in the general population, are decreased within the TME of PWH. Our data suggest that HIV-associated HNC is associated with poorer outcomes and highlight differences in tumor biology that require further detailed characterization in large cohorts. more...
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- 2022
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27. Patients with HIV-associated cancers have evidence of increased T cell dysfunction and exhaustion prior to cancer diagnosis
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Omkar Chaudhary, Diane Trotta, Kaicheng Wang, Xun Wang, Xiuping Chu, Chip Bradley, Jason Okulicz, Ryan C Maves, Karl Kronmann, Christina M Schofield, Jason M Blaylock, Yanhong Deng, Kurt A Schalper, Susan M Kaech, Brian Agan, Anuradha Ganesan, and Brinda Emu more...
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Pharmacology ,Cancer Research ,Oncology ,Case-Control Studies ,Neoplasms ,Programmed Cell Death 1 Receptor ,Immunology ,HIV-1 ,Humans ,Molecular Medicine ,Immunology and Allergy ,HIV Infections ,Biomarkers - Abstract
BackgroundPeople living with HIV (PLWH) have increased risk of developing cancers after controlling traditional risk factors and viral suppression. This study explores whether T cells can serve as a marker of risk for cancer among HIV-infected virally suppressed patients.MethodsA nested case control study design was pursued with 17 cancer cases and 73 controls (PLWH without cancer)ouidentified among the US Military HIV Natural History Study cohort, and were matched for CD4 + count, duration of HIV infection, and viral suppression. Cells were obtained from PLWH on an average of 12 months prior to clinical cancer diagnosis. Expression of inhibitory receptors (PD-1, CD160, CD244, Lag-3, and TIGIT), and transcription factors (T-bet, Eomesodermin, TCF-1, and (TOX) was measured on CD8 +T cells from that early time point.ResultsWe found that cases have increased expression of PD-1 +CD160+CD244+ (‘triple positive’) on total and effector CD8 + compared with controls (p=0.02). Furthermore, CD8 +T cells that were both PD-1 +CD160+CD244+ and T-betdimEomeshi were significantly elevated in cases at time point before cancer detection, compared with controls without cancer (p=0.008). This was driven by the finding that transcriptional factor profile of cells was altered in cancers compared with controls. Triple-positive cells were noted to retain the ability for cytotoxicity and cytokine secretion mediated by expression of CD160 and PD-1, respectively. However, triple-positive cells demonstrated high expression of TOX-1, a transcription factor associated with T cell exhaustion.ConclusionIn conclusion, we have found a subset of dysfunctional CD8 +T cells, PD-1 +CD160+CD244+T-betdimEomeshi, that is elevated 12 months before cancer diagnosis, suggesting that peripheral T cell alterations may serve as a biomarker of increased cancer risk among PLWH. more...
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- 2022
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28. Oxidized Lipids and CD36-Mediated Lipid Peroxidation in CD8 T Cells Suppress Anti-Tumor Immune Responses
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Michael Downes, Joseph L. Witztum, Nada A. Abumrad, Bryan McDonald, Antonio Pinto, Susan M. Kaech, Ping-Chih Ho, Maxim N. Shokhirev, Xiaoli Sun, Shihao Xu, Dan Chen, Taha Merghoub, Jun Siong Low, Patricia Rodríguez-Morales, Ronald M. Evans, Victoria Tripple, Brinda Emu, Haiping Wang, Yagmur Farsakoglu, Jedd D. Wolchok, Siva Karthik Varanasi, April Williams, Ziyan Xu, Omkar Chaudhary, Roberta Zappasodi, Wenxi Tang, and Guoliang Cui more...
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biology ,Chemistry ,CD36 ,T cell ,hemic and immune systems ,GPX4 ,Cell biology ,Lipid peroxidation ,chemistry.chemical_compound ,Immune system ,medicine.anatomical_structure ,biology.protein ,medicine ,Cytotoxic T cell ,lipids (amino acids, peptides, and proteins) ,Scavenger receptor ,CD8 - Abstract
SummaryT cell metabolic fitness plays a pivotal role in anti-tumor immunity and metabolic deregulation causes T cell dysfunction (i.e., ‘exhaustion’) in cancer. We identify that the scavenger receptor CD36 limits anti-tumor CD8+T cell effector functions through lipid peroxidation. In murine tumors, oxidized phospholipids (OxPLs) were highly abundant and CD8+TILs increased uptake and accumulation of lipids and lipid peroxidation. Functionally ‘exhausted’ CD8+TILs substantially increased CD36 expression and CD36-deficient CD8+TILs had more robust anti-tumor activity and cytokine production than wild-type cells. We further show that CD36 promotes uptake of oxidized low-density lipoproteins (OxLDL) and induces lipid peroxidation in CD8+TILs, and OxLDL inhibits CD8+T cell functions in a CD36-dependent manner. Moreover, glutathione peroxidase 4 (GPX4) over-expression lowers lipid peroxidation and restores functionalities in CD8+TILs. These results define a key role for an oxidized lipid-CD36 axis in promoting intratumoral CD8+T cell dysfunction. more...
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- 2020
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29. Uptake of oxidized lipids by the scavenger receptor CD36 promotes lipid peroxidation and dysfunction in CD8+ T cells in tumors
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Taha Merghoub, Michael Downes, Xiaoli Sun, Shihao Xu, Jun Siong Low, April Williams, Yagmur Farsakoglu, Antonio Pinto, Ziyan Xu, Omkar Chaudhary, Ping-Chih Ho, Dan Chen, Wenxi Tang, Bryan McDonald, Roberta Zappasodi, Brinda Emu, Ronald M. Evans, Jedd D. Wolchok, Maxim N. Shokhirev, Susan M. Kaech, Joseph L. Witztum, Haiping Wang, Nada A. Abumrad, Siva Karthik Varanasi, Isabell Schulze, Guoliang Cui, Patricia Rodríguez-Morales, and Victoria Tripple more...
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0301 basic medicine ,Tumor microenvironment ,biology ,Tumor-infiltrating lymphocytes ,CD36 ,Immunology ,hemic and immune systems ,GPX4 ,Lipid peroxidation ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,Infectious Diseases ,chemistry ,030220 oncology & carcinogenesis ,Cancer research ,biology.protein ,Immunology and Allergy ,Cytotoxic T cell ,lipids (amino acids, peptides, and proteins) ,Scavenger receptor ,CD8 - Abstract
Summary A common metabolic alteration in the tumor microenvironment (TME) is lipid accumulation, a feature associated with immune dysfunction. Here, we examined how CD8+ tumor infiltrating lymphocytes (TILs) respond to lipids within the TME. We found elevated concentrations of several classes of lipids in the TME and accumulation of these in CD8+ TILs. Lipid accumulation was associated with increased expression of CD36, a scavenger receptor for oxidized lipids, on CD8+ TILs, which also correlated with progressive T cell dysfunction. Cd36−/− T cells retained effector functions in the TME, as compared to WT counterparts. Mechanistically, CD36 promoted uptake of oxidized low-density lipoproteins (OxLDL) into T cells, and this induced lipid peroxidation and downstream activation of p38 kinase. Inhibition of p38 restored effector T cell functions in vitro, and resolution of lipid peroxidation by overexpression of glutathione peroxidase 4 restored functionalities in CD8+ TILs in vivo. Thus, an oxidized lipid-CD36 axis promotes intratumoral CD8+ T cell dysfunction and serves as a therapeutic avenue for immunotherapies. more...
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- 2021
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30. Clinically significant mutations in HIV-infected patients with lung adenocarcinoma
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Jonathan Thaler, Kristina Crothers, Mary Beth Beasley, Carlie S. Sigel, Juan P. Wisnivesky, Keith Sigel, Joshua Bauml, Kristen Hysell, Laetitia Borsu, and Brinda Emu
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0301 basic medicine ,Oncology ,Male ,Cancer Research ,Lung Neoplasms ,HIV Infections ,medicine.disease_cause ,Genetics & Genomics ,Cohort Studies ,0302 clinical medicine ,epidermal growth factor receptor mutation ,Cause of death ,virus diseases ,Middle Aged ,Prognosis ,3. Good health ,ErbB Receptors ,Survival Rate ,030220 oncology & carcinogenesis ,Cohort ,Adenocarcinoma ,Female ,KRAS ,Cohort study ,medicine.medical_specialty ,oncogenic mutations ,Proto-Oncogene Proteins p21(ras) ,03 medical and health sciences ,Internal medicine ,medicine ,Biomarkers, Tumor ,Humans ,Lung cancer ,Survival rate ,non-small cell lung cancer ,Neoplasm Staging ,adenocarcinoma ,business.industry ,Cancer ,HIV ,medicine.disease ,digestive system diseases ,respiratory tract diseases ,030104 developmental biology ,Mutation ,HIV-1 ,business ,Follow-Up Studies - Abstract
Background: Lung cancer is a major cause of death in HIV-infected (HIV+) persons. In this study, we compared the prevalence of tumour EGFR and KRAS mutations in a cohort of lung adenocarcinoma patients by HIV status. Methods: We collected data from 55 HIV+ patients with lung adenocarcinoma matched to 136 uninfected comparators. We compared the prevalence of EGFR and KRAS mutations by HIV status. We then compared survival by HIV status and by cancer mutation status among HIV+ subjects. Results: Presence of KRAS and EGFR genetic alterations did not vary by HIV status (all P>0.1). There was no difference in overall survival by HIV status or by mutation status among HIV+ subjects. Conclusions: We found no major differences in the prevalence of EGFR or KRAS lung adenocarcinoma mutations by HIV status, suggesting that mutational testing should be conducted similarly regardless of the HIV status. more...
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- 2017
31. Exosomal MicroRNAs Associate With Neuropsychological Performance in Individuals With HIV Infection on Antiretroviral Therapy
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Richard W. Price, Lingeng Lu, Rabib Chaudhury, Yong Kong, Brinda Emu, Xinran Liu, Tess OʼMeara, Jennifer Chiarella, Kevin Robertson, and Serena Spudich
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Cart ,Oncology ,Adult ,Male ,medicine.medical_specialty ,Cross-sectional study ,Anti-HIV Agents ,Clinical Sciences ,Neurocognitive Disorders ,Inflammation ,HIV Infections ,exosomes ,Neuropsychological Tests ,Exosomes ,Article ,Pharmacotherapy ,Drug Therapy ,HIV-associated neurocognitive dysfunction ,Internal medicine ,Virology ,microRNA ,medicine ,Genetics ,Humans ,Pharmacology (medical) ,business.industry ,axon guidance ,Neuropsychology ,Neurosciences ,Phlebotomy ,Middle Aged ,Chronic infection ,MicroRNAs ,Cross-Sectional Studies ,Mental Health ,Infectious Diseases ,inflammation ,Combination ,Public Health and Health Services ,HIV/AIDS ,Drug Therapy, Combination ,Female ,medicine.symptom ,business ,Infection ,Signal Transduction ,Biotechnology - Abstract
Background Neurocognitive dysfunction remains prevalent among people living with HIV (PLWH), even after viral suppression on combination antiretroviral therapy (cART). We investigated associations between neuropsychological performance (NP) and patterns of circulating exosomal microRNA (exo-miRNA) expression in PLWH on cART. Setting A cross-sectional examination of plasma exo-miRNA among PLWH on cART with systemic viral suppression and volunteers without HIV infection. Methods Thirty-one PLWH who started cART during early infection (n = 19) or chronic infection (n = 12) participated in phlebotomy and an 11-test neuropsychological battery after >1 year on treatment. NP higher- or lower-performing participants were categorized based on normalized neuropsychological scores. Total RNA was extracted from purified exosomes of 31 PLWH and 5 volunteers without HIV and subject to small RNA sequencing. Differential expression of exo-miRNAs was examined and biological functions were predicted. Results Eleven exo-miRNAs were up-regulated in NP lower-performing (n = 18) relative to higher-performing PLWH (n = 13). A high proportion of the differentiating exo-miRNA target the axon guidance KEGG pathway and neurotrophin tyrosine receptor kinase signaling Gene Ontology pathway. Differential expression analysis of exo-miRNAs between NP lower- (n = 7) and higher-performing (n = 12) PLWH within the early infection group alone confirmed largely consistent findings. Conclusions Plasma exo-miRNA content differed between NP higher- and lower-performing PLWH. Several differentially expressed exo-miRNAs were predicted to be involved in inflammation and neurodegeneration pathways. Exo-miRNA in plasma may indicate cross-talk between the circulation and central nervous system and thus may be clinically relevant for neurocognitive dysfunction in PLWH. more...
- Published
- 2019
32. Assessment of the Safety of Pembrolizumab in Patients With HIV and Advanced Cancer-A Phase 1 Study
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Judith C Kaiser, Priscila H. Goncalves, Robert Yarchoan, Ramya Ramaswami, Andreanne M. Lacroix, Lawrence Fong, Steven P. Fling, Maher Abdul-Hay, Martin A. Cheever, Thomas S. Uldrick, Marc S. Ernstoff, Steve Young Lee, Elad Sharon, Alisa J Claeys, Lisa Lundgren, Kathryn Lurain, Sharavi Peeramsetti, Mario Sznol, Brinda Emu, Chia-Ching Jackie Wang, and Christopher H Parsons more...
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Cancer Research ,medicine.medical_specialty ,business.industry ,Common Terminology Criteria for Adverse Events ,Pembrolizumab ,medicine.disease ,Clinical trial ,03 medical and health sciences ,0302 clinical medicine ,Oncology ,Tolerability ,030220 oncology & carcinogenesis ,Internal medicine ,Medicine ,030212 general & internal medicine ,business ,Adverse effect ,Lung cancer ,Viral load ,Progressive disease ,Original Investigation - Abstract
Importance Anti-PD-1 (anti-programmed cell death 1) and anti-PD-L1 (anti-programmed cell death ligand 1) regimens are preferred therapies for many cancers, including cancers associated with HIV. However, patients with HIV were excluded from most registered trials. Objective The primary objective was to evaluate the safety of pembrolizumab in people with HIV and advanced cancer; the secondary objective was to evaluate tumor responses. Design, setting, and participants Open-label, nonrandomized, phase 1 multicenter study conducted at 7 Cancer Immunotherapy Trials Network sites. Patients with HIV and advanced cancer as well as a CD4 count greater than or equal to 100 cells/μL, antiretroviral therapy (ART) for 4 or more weeks, and an HIV viral load of less than 200 copies/mL were eligible. Exclusion criteria included uncontrolled hepatitis B or C infection, active immunosuppressive therapy, or a history of autoimmune disease requiring systemic therapy. Interventions Pembrolizumab, 200 mg, administered intravenously every 3 weeks for up to 35 doses in 3 CD4 count-defined cohorts. Participants continued ART. Main outcomes and measures Safety and tolerability were assessed using current NCI Common Terminology Criteria for Adverse Events. Immune-related adverse events grade 2 or higher were considered immune-related events of clinical interest (irECI). Tumor responses were evaluated using standard tumor-specific criteria. Results Thirty participants (28 men and 2 women; median [range] age, 57 [39-77] years) were enrolled from April 2016 through March 2018; 6 had Kaposi sarcoma (KS), 5 had non-Hodgkin lymphoma (NHL), and 19 had non-AIDS-defining cancers. Safety was observed over 183 cycles of treatment with pembrolizumab. Most treatment-emergent adverse events at least possibly attributed to pembrolizumab were grade 1 or 2 (n = 22), and 20% (n = 6) were grade 3. The irECI included hypothyroidism (6 participants), pneumonitis (3 participants), rash (2 participants), an elevated aminotransferase/alanine aminotransferase level (1 participant), and a musculoskeletal event (1 participant). One participant with pretreatment KS herpesvirus (KSHV) viremia developed a polyclonal KSHV-associated B-cell lymphoproliferation and died. HIV was controlled in all participants. Increases in CD4 count were not statistically significant (median increase, 19 cells/μL; P = .18). Best tumor responses included complete response (lung, 1 patient), partial response (NHL, 2 patients), stable disease for 24 weeks or more (KS, 2 patients), stable disease for less than 24 weeks (15 patients), and progressive disease (8 patients); 2 patients were not evaluable. Conclusions and relevance Pembrolizumab has acceptable safety in patients with cancer, HIV treated with ART, and a CD4+ T-cell count of greater than 100 cells/μL but may be associated with KSHV-associated B-cell lymphoproliferation. Clinical benefit was noted in lung cancer, NHL, and KS. Anti-PD-1 therapy is appropriate for US Food and Drug Administration-approved indications and clinical trials in this population. Trial registration ClinicalTrials.gov identifier: NCT02595866. more...
- Published
- 2019
33. Phase 3 Study of Ibalizumab for Multidrug-Resistant HIV-1
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Sandra Win, Steven Weinheimer, Gary Richmond, Christian Marsolais, Stanley Lewis, Brinda Emu, Jeffrey Fessel, Shannon Schrader, and Princy Kumar
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0301 basic medicine ,Adult ,Diarrhea ,Male ,medicine.drug_class ,Anti-HIV Agents ,Human immunodeficiency virus (HIV) ,Phases of clinical research ,HIV Infections ,Drug resistance ,medicine.disease_cause ,Monoclonal antibody ,03 medical and health sciences ,Young Adult ,Drug Resistance, Multiple, Viral ,HIV Fusion Inhibitors ,medicine ,Humans ,Aged ,Ibalizumab ,biology ,business.industry ,Antibodies, Monoclonal ,General Medicine ,Middle Aged ,Viral Load ,Virology ,CD4 Lymphocyte Count ,Multiple drug resistance ,030104 developmental biology ,Injections, Intravenous ,biology.protein ,HIV-1 ,Drug Therapy, Combination ,Female ,Antibody ,business ,Viral load ,medicine.drug - Abstract
Ibalizumab, a humanized IgG4 monoclonal antibody, blocks the entry of human immunodeficiency virus type 1 (HIV-1) by noncompetitive binding to CD4.In this single-group, open-label, phase 3 study, we enrolled 40 adults with multidrug-resistant (MDR) HIV-1 infection in whom multiple antiretroviral therapies had failed. All the patients had a viral load of more than 1000 copies of HIV-1 RNA per milliliter. After a 7-day control period in which patients continued to receive their current therapy, a loading dose of 2000 mg of ibalizumab was infused; the viral load was quantified 7 days later. Through week 25 of the study, patients received 800 mg of ibalizumab every 14 days, combined with an individually optimized background regimen including at least one fully active agent. The primary end point was the proportion of patients with a decrease in viral load of at least 0.5 logA total of 31 patients completed the study. The mean baseline viral load was 4.5 logIn patients with MDR HIV-1 infection who had advanced disease and limited treatment options, ibalizumab had significant antiviral activity during a 25-week study. Evidence of the emergence of diminished ibalizumab susceptibility was observed in vitro in patients who had virologic failure. (Funded by the Orphan Products Clinical Trials Grants Program of the Food and Drug Administration and TaiMed Biologics; TMB-301 ClinicalTrials.gov number, NCT02475629 .). more...
- Published
- 2018
34. HIV and Age Do Not Synergistically Affect Age-Related T-Cell Markers
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Amy C. Justice, Matthew Bidwell Goetz, Emilie Jalbert, Robert Dubrow, Yanhong Deng, Brinda Emu, Lesley S. Park, and Shelli F. Farhadian
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0301 basic medicine ,CD4-Positive T-Lymphocytes ,Male ,Aging ,HIV Infections ,CD8-Positive T-Lymphocytes ,0302 clinical medicine ,T-Lymphocyte Subsets ,80 and over ,Cytotoxic T cell ,2.1 Biological and endogenous factors ,Pharmacology (medical) ,030212 general & internal medicine ,Aetiology ,Veterans ,Aged, 80 and over ,education.field_of_study ,medicine.diagnostic_test ,virus diseases ,Viral Load ,Middle Aged ,Flow Cytometry ,medicine.anatomical_structure ,Infectious Diseases ,Anti-Retroviral Agents ,Public Health and Health Services ,HIV/AIDS ,Infection ,Cohort study ,Adolescent ,T cell ,Population ,Clinical Sciences ,T cells ,and over ,Article ,Flow cytometry ,Immunophenotyping ,03 medical and health sciences ,Young Adult ,Immune system ,Clinical Research ,Virology ,medicine ,Humans ,education ,Aged ,business.industry ,HIV ,030104 developmental biology ,Good Health and Well Being ,Cross-Sectional Studies ,Immunology ,Serostatus ,business ,CD8 - Abstract
Author(s): Farhadian, Shelli; Jalbert, Emilie; Deng, Yanhong; Goetz, Matthew B; Park, Lesley S; Justice, Amy C; Dubrow, Robert; Emu, Brinda | Abstract: IntroductionDespite major progress in controlling HIV disease through antiretroviral therapy, changes in immune phenotype and function persist in individuals with chronic HIV, raising questions about accelerated aging of the immune system.MethodsWe conducted a cross-sectional study (2005-2007) of HIV-infected (n = 111) and uninfected (n = 114) men from the Veterans Aging Cohort Study. All HIV-infected subjects were on antiretroviral therapy with VL l400 copies/mL for at least 3 years. T-cell markers were examined using flow cytometry. We evaluated the impact of HIV serostatus and age on T-cell phenotypes (expressed as percentages of the total CD4 and CD8 T-cell population) using multivariate linear regression, adjusted for smoking, alcohol, and race/ethnicity. We tested for interactions between HIV and age by including interaction terms.ResultsAmong both HIV-infected and uninfected subjects, increasing age was associated with a decreased proportion of naive CD4 T cells (P = 0.014) and CD8 T cells (P l 0.0001). Both HIV infection and increasing age were associated with higher proportions of effector memory CD4 T cells (P l 0.0001 for HIV; P = 0.04 for age) and CD8 T cells (P = 0.0001 for HIV; P = 0.0004 for age). HIV infection, but not age, was associated with a higher proportion of activated CD8 T cells (P l 0.0001). For all T-cell subsets tested, there were no significant interactions between HIV infection and age.ConclusionsAge and HIV status independently altered the immune system, but we found no conclusive evidence that HIV infection and advancing age synergistically result in accelerated changes in age-associated T-cell markers among virally suppressed individuals. more...
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- 2018
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35. Phase 1 Randomized, Double-Blind, Placebo-Controlled Study of RG7667, an Anticytomegalovirus Combination Monoclonal Antibody Therapy, in Healthy Adults
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Michael A. Derby, Rong Deng, X. Charlene Liao, Ashley E. Fouts, Jorge A. Tavel, Mauricio Maia, Becket Feierbach, Tracy Burgess, Brinda Emu, Julie H. Ishida, and Pearline A. Brown
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Adult ,Male ,Placebo-controlled study ,Cytomegalovirus ,Pharmacology ,Placebo ,Antiviral Agents ,Double-Blind Method ,Pharmacokinetics ,Humans ,Medicine ,Pharmacology (medical) ,Monoclonal antibody therapy ,Dose-Response Relationship, Drug ,biology ,business.industry ,Immunogenicity ,Antibodies, Monoclonal ,Entry into host ,Healthy Volunteers ,Infectious Diseases ,Tolerability ,biology.protein ,Drug Therapy, Combination ,Female ,Antibody ,business ,Half-Life - Abstract
Cytomegalovirus can cause debilitating and life-threatening disease in newborns infected in utero and immunocompromised individuals, including transplant recipients. RG7667 is a unique combination of two monoclonal antibodies that binds glycoprotein complexes on the surface of cytomegalovirus and inhibits its entry into host cells. A phase 1 first-in-human, randomized, double-blind, placebo-controlled, dose-escalation study of RG7667 given intravenously was conducted in 181 healthy adults. The study involved a single ascending dose stage (1, 3, 5, and 10 mg/kg each antibody; n = 21), a multiple ascending dose stage (5 and 10 mg/kg each antibody monthly for 3 doses; n = 10), and a multiple dose expansion stage (10 mg/kg each antibody monthly for 3 doses; n = 150). Subjects were followed for 85 to 141 days to evaluate safety, tolerability, pharmacokinetics, and immunogenicity. Most adverse events were mild, and the incidence of adverse events was similar among the RG7667 and placebo groups. RG7667 had dose-proportional pharmacokinetics in all three dosing stages, a mean terminal half-life of 20 to 30 days, and an overall pharmacokinetic profile consistent with that of a human monoclonal antibody that lacks endogenous host targets. The proportion of subjects developing an antitherapeutic antibody response was not higher in the RG7667 group than in the placebo group. In summary, single and multiple doses of RG7667 were found to be safe and well-tolerated in healthy adults and had a favorable pharmacokinetic and immunogenicity profile. This study supports further development of RG7667 as a therapy for the prevention and treatment of cytomegalovirus infection in susceptible populations. (This study has been registered at ClinicalTrials.gov under registration no. NCT01496755.) more...
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- 2015
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36. Photo Quiz: Peripheral Blood Smear in a Ugandan Refugee
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Onyema Ogbuagu, Benjamin A. Rodwin, Raffaele Bernardo, Jaimie P. Meyer, Shoshana Streiter, Amir M. Mohareb, Brinda Emu, and Perry Tiberio
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Microbiology (medical) ,medicine.medical_specialty ,rhinorrhea ,business.industry ,General surgery ,Refugee ,fungi ,food and beverages ,Photo Quiz ,Peripheral blood ,Surgery ,Lethargy ,parasitic diseases ,medicine ,Chills ,medicine.symptom ,business - Abstract
A 22-year-old man presented to our hospital with a 10-day history of a frontal headache, chills, and lethargy, associated with rhinorrhea and a nonproductive cough. The patient was originally from the Democratic Republic of Congo and had been living in a refugee camp in Uganda, near Kampala, for the more...
- Published
- 2017
37. Case report of the patient source of the Babesia microti R1 reference strain and implications for travelers
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Emmanuel Cornillot, Peter J. Krause, Laurence Berry, Vasilica Ciubotaru, Choukri Ben Mamoun, Brinda Emu, Philipp Stahl, Yves Poinsignon, Pascal Pouedras, Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA), Dynamique des interactions membranaires normales et pathologiques (DIMNP), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut de Biologie Computationnelle (IBC), Institut National de la Recherche Agronomique (INRA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Bretagne Atlantique [Vannes], CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Montpellier (UM)-Institut National de la Recherche Agronomique (INRA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS), and Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Montpellier 1 (UM1) more...
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0301 basic medicine ,Male ,animal diseases ,tick-borne disease ,MESH: Tick Bites ,law.invention ,MESH: Babesia microti ,0302 clinical medicine ,Ticks ,law ,MESH: Animals ,MESH: Travel ,Polymerase chain reaction ,MESH: Aged ,Tick-borne disease ,Travel ,biology ,medicine.diagnostic_test ,Babesiosis ,General Medicine ,3. Good health ,MESH: Babesiosis ,Massachusetts ,R1 strain ,France ,Antibody ,MESH: Massachusetts ,030231 tropical medicine ,Physical examination ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Tick ,Babesia microti ,03 medical and health sciences ,parasitic diseases ,medicine ,Animals ,Humans ,Medical history ,MESH: Ticks ,Aged ,MESH: Humans ,Tick Bites ,business.industry ,Original Articles ,medicine.disease ,biology.organism_classification ,Virology ,MESH: Male ,MESH: France ,030104 developmental biology ,Babesia ,biology.protein ,business ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology - Abstract
BackgroundIn 2002, a previously healthy 69-year-old man travelled to France from the United States and presented to our hospital with a febrile illness that subsequently was determined to be babesiosis. The blood isolated from this patient served as a source for propagation of the Babesia microti R1 strain with subsequent sequencing and annotation of the parasite genome.MethodsUpon admission, we obtained a medical history, performed a physical examination, and examined his blood for the presence of a blood borne pathogen by microscopy, PCR and indirect immunofluorescence antibody testing. Once the diagnosis of babesiosis was made, we reviewed the literature to assess the distribution of B. microti-associated babesiosis cases in immunocompetent patients from outside the USA.ResultsThe patient recalled a tick bite during the previous month on Cape Cod, Massachusetts. The diagnosis was confirmed by identification of Babesia-infected red blood cells on blood smears, amplification of B. microti DNA in blood by PCR and the presence of B. microti antibody in the serum. This strain was the first isolate of B. microti to be fully sequenced and its annotated genome serves as a reference for molecular and cell biology studies aimed at understanding B. microti pathophysiology and developing diagnostic tests and therapies. A review of babesiosis cases demonstrates a worldwide distribution of B. microti and identifies potential emerging endemic areas where travelers may be at risk of contracting B. microti infection.ConclusionThis case provides clinical information about the patient infected with the R1 isolate and a review of travel risk, diagnosis and treatment of babesiosis in endemic and non-endemic areas. more...
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- 2017
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38. 661. Ibalizumab Efficacy and Safety Through 48 Weeks of Treatment: Results of an Expanded Access Protocol (TMB-311)
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Edwin DeJesus, Catherine Creticos, Brinda Emu, Jason Leider, Steve Weinheimer, Mezgebe Berhe, and Zvi Cohen
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Protocol (science) ,medicine.medical_specialty ,Ibalizumab ,business.industry ,Treatment results ,Abstracts ,Infectious Diseases ,Oncology ,Viral Load result ,Internal medicine ,Expanded access ,Poster Abstracts ,Medicine ,Viral suppression ,business ,medicine.drug - Abstract
Background Ibalizumab (IBA), a humanized monoclonal antibody, is the first CD4-directed post-attachment HIV-1 inhibitor. It was approved by the FDA in March 2018 based on results from the pivotal Phase 3 TMB-301 clinical study. The TMB-311 expanded access protocol Cohort 2 enrolled treatment-experienced patients with multidrug-resistant (MDR) HIV-1 infection to further evaluate the efficacy, safety and tolerability of IBA in combination with an optimized background regimen (OBR). Here, we report the results through 48 weeks of treatment in these patients. Methods Major eligibility criteria included HIV-1 viral load (VL) >1000 copies/mL, resistance to ≥1 antiretroviral (ARV) medication from three different ARV classes and full viral sensitivity to ≥1 ARV agent. Treatment started with IBA 2000 mg intravenously (IV) on Day 0 and then 800 mg IV (maintenance) every 2 weeks thereafter. OBR with ≥1 fully active agent also started at Day 0. Results Cohort 2 enrolled 38 patients with a median age of 53 years, mostly male (87%) and white (53%). At Baseline, median VL was 4.7 log10 copies/mL, CD4 cell count was 26 cells/mm3 and overall susceptibility score of 1. A ≥0.5 log10 decrease in VL from Baseline was achieved in 28 of 37 patients (76%) at Day 7. Of 24 patients who completed the Week 24 visit, 11 (46%) had HIV-1 RNA levels Conclusion Results from Cohort 2 patients of TMB-311 (IBA + OBR) demonstrate durable viral suppression in this difficult-to-treat patient population and with a safety profile consistent with pivotal Phase 3 study of IBA. Disclosures All authors: No reported disclosures. more...
- Published
- 2019
39. P1.04-23 Characterizing the Tumor Immune Microenvironment of Non-Small Cell Lung Carcinoma in People Living with HIV Using Imaging Mass Cytometry
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R. Yusuf, F. Villarroel-Espindola, Kurt A. Schalper, and Brinda Emu
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Pulmonary and Respiratory Medicine ,Lung ,business.industry ,Immune microenvironment ,Human immunodeficiency virus (HIV) ,medicine.disease_cause ,medicine.disease ,medicine.anatomical_structure ,Oncology ,Carcinoma ,Cancer research ,Medicine ,Mass cytometry ,Non small cell ,business - Published
- 2019
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40. Phase I study of pembrolizumab in people with HIV and cancer
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Steve Young Lee, Chia-Ching Jackie Wang, Marc S. Ernstoff, Elad Sharon, Martin A. Cheever, Thomas S. Uldrick, Lawrence Fong, Kathryn Lurain, Alisa J Claeys, Ramya Ramaswami, Holbrook E Kohrt, Judith C Kaiser, Chris Parsons, Priscila H. Goncalves, Andreanne M. Lacroix, Robert Yarchoan, Brinda Emu, Lisa Lundgren, Mohammad Maher Abdul Hay, and Sharavi Peeramsetti more...
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Human immunodeficiency virus (HIV) ,Cancer ,Pembrolizumab ,medicine.disease_cause ,medicine.disease ,Phase i study ,03 medical and health sciences ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,business ,030215 immunology - Abstract
2500 Background: People with HIV have been excluded from immuno-oncology (IO) studies. Anti- PD-1/PD-L1 therapies are approved for a growing number of cancers. We evaluated pembrolizumab (pembro) in people with HIV and cancer. Methods: CITN-12 is a multicenter phase 1 trial. Key eligibility: advanced cancer; ECOG ≤1; CD4 ≥100 cells/μL; ≥4 weeks antiretroviral therapy (ART), HIV viral load (VL) < 200 copies/mL. Exclusion: uncontrolled HBV/HCV, autoimmune disease. Participants (pts) accrued into CD4 based cohorts (C): C1 100-199; C2 200-350; C3 > 350 CD4 cells/μL. Pembro 200 mg IV administered Q3W for up to 35 doses. Adverse events (AE) evaluated by CTCAE. Immune related AE ≥ grade (Gr) 2 were events of clinical interest (irECI). Clinical benefit (tumor shrinkage or stable disease [SD] ≥24 weeks) was estimated. Data were locked for safety analysis and publication once C2 and C3 completed accrual and all pts completed ≥2 cycles. Accrual continued for 6 C1 pts and a new phase 1b Kaposi sarcoma (KS) cohort (C4). Results: 30 pts, characteristics: C1 (6), C2 and 3 (12 each), median (med) age 57 years (range 39-77), 28 men, 2 women, 60% White, 30% Black, 10% Hispanic. Med CD4 285 cells/μL (132 - 966). Cancers: KS (6), non-Hodgkin lymphoma (NHL) (5), non-AIDS defining (19) – most common: anal (6) and squamous cell skin (3). Prior radiation (19), med prior systemic therapies 2 (0-8). Safety observed over 183 cycles, med 5 (1-32). Treatment emergent AE ≥ possibly attributed to pembro mostly Gr 1-2, with 20% of pts having Gr 3. irECI: hypothyroidism (6), elevated AST/ALT (1), pneumonitis (3), rash (2), musculoskeletal (1).1 KS pt developed KSHV-associated multicentric Castleman disease (KSHV-MCD) and died of the AE. HIV was controlled and increasing CD4 counts were observed. Best response: complete (lung, 1), partial (NHL, 2), SD ≥24 weeks (KS, 2), SD < 24 weeks (13), progressive disease (10), not evaluable (2). Conclusions: Pembro has acceptable safety in cancer pts with HIV on ART and > 100 CD4 cells/µL, similar to patients without HIV. Anti-PD-1 may unmask KSHV-MCD and such KSHV-viremic patients should be excluded. Clinical benefit was noted in several tumor types. Anti-PD1 is appropriate for FDA-approved indications in this population. Patients with HIV meeting appropriate eligibility criteria should be included in IO studies. Clinical trial information: NCT02595866. more...
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- 2019
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41. Epigenome-wide differential DNA methylation between HIV-infected and uninfected individuals
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Guilin Wang, Richard E. Sutton, Ying Hu, John H. Krystal, Ke Xu, Brinda Emu, Amy C. Justice, Eric O. Johnson, Xinyu Zhang, Zuoheng Wang, and Hongyu Zhao
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0301 basic medicine ,NLRC5 ,Cancer Research ,DNA methylation ,biology ,Methylation ,Epigenome ,HIV-1 infection ,Major histocompatibility complex ,Virology ,3. Good health ,viral load ,03 medical and health sciences ,030104 developmental biology ,CpG site ,Immunology ,biology.protein ,Epigenome-wide association ,Epigenetics ,Molecular Biology ,Gene ,Viral load ,Research Paper - Abstract
Epigenetic control of human immunodeficiency virus-1 (HIV-1) genes is critical for viral integration and latency. However, epigenetic changes in the HIV-1-infected host genome have not been well characterized. Here, we report the first large-scale epigenome-wide association study of DNA methylation for HIV-1 infection. We recruited HIV-infected (n = 261) and uninfected (n = 117) patients from the Veteran Aging Cohort Study (VACS) and all samples were profiled for 485,521 CpG sites in DNA extracted from the blood. After adjusting for cell type and clinical confounders, we identified 20 epigenome-wide significant CpGs for HIV-1 infection. Importantly, 2 CpGs in the promoter of the NLR family, CARD domain containing gene 5 (NLRC5), a key regulator of major histocompatibility complex class I gene expression, showed significantly lower methylation in HIV-infected subjects than in uninfected subjects (cg07839457: t = −6.03, Pnominal = 4.96 × 10−9; cg16411857: t = −7.63, Pnominal = 3.07 × 10−13). Hypomethylation of these 2 CpGs was replicated in an independent sample (GSE67705: cg07839457: t = −4.44, Pnominal = 1.61 × 10−5; cg16411857: t = −5.90; P = 1.99 × 10−8). Methylation of these 2 CpGs in NLRC5 was negatively correlated with viral load in the 2 HIV-infected samples (cg07839457: P = 1.8 × 10−4; cg16411857: P = 0.03 in the VACS; and cg07839457: P = 0.04; cg164111857: P = 0.01 in GSE53840). Our findings demonstrate that differential DNA methylation is associated with HIV infection and suggest the involvement of a novel host gene, NLRC5, in HIV pathogenesis. more...
- Published
- 2016
42. Interim safety analysis of cancer immunotherapy trials Network – 12 (CITN-12): a Phase 1 study of pembrolizumab in patients with HIV and cancer
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K. Aleman, Brinda Emu, Lisa Lundgren, Andreanne M. Lacroix, Kathryn Lurain, Frank Maldarelli, Thomas S. Uldrick, Judith C Kaiser, Steven P. Fling, Chris Parsons, Elad Sharon, M. Lindsley, Robert J. Gorelick, Marc S. Ernstoff, Anaida Widell, Holbrook E Kohrt, Priscila H. Goncalves, M.A. ‘Mac’ Cheever, and Robert Yarchoan more...
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,Epidemiology ,medicine.medical_treatment ,Immunology ,Human immunodeficiency virus (HIV) ,Pembrolizumab ,medicine.disease_cause ,Microbiology ,03 medical and health sciences ,Cancer immunotherapy ,Virology ,Internal medicine ,Interim ,medicine ,In patient ,business.industry ,Public Health, Environmental and Occupational Health ,Cancer ,medicine.disease ,QR1-502 ,030104 developmental biology ,Infectious Diseases ,Public aspects of medicine ,RA1-1270 ,business - Published
- 2017
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43. Forty-eight-Week Safety and Efficacy On-Treatment Analysis of Ibalizumab in Patients with Multi-Drug Resistant HIV-1
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Sandra Win, Christian Marsolais, Princy Kumar, Brinda Emu, W. Jeffery Fessel, Steven Weinheimer, Shannon Schrader, Stanley Lewis, and Gary Richmond
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0301 basic medicine ,medicine.medical_specialty ,Ibalizumab ,Emu family ,business.industry ,030106 microbiology ,Human immunodeficiency virus (HIV) ,medicine.disease_cause ,03 medical and health sciences ,Abstracts ,Infectious Diseases ,Oncology ,Pharmacokinetics ,Viral Load result ,Internal medicine ,Oral Abstract ,medicine ,Multi drug resistant ,In patient ,Viral suppression ,business ,medicine.drug - Abstract
Background Management of multi-drug-resistant (MDR) HIV-1 remains a challenge. The advent of antiretroviral (ARVs) with novel mechanisms of action are needed to expand therapeutic options for MDR patients. Ibalizumab (IBA) is a humanized monoclonal antibody with a unique binding specificity to the CD4 domain 2, allowing it to block viral entry into host cells without CD4 depletion. Patients completing the 24-week Phase 3 study (TMB-301) continued treatment in study TMB-311. Here, we report the durable efficacy and long-term safety of IBA with an optimized background regimen (OBR) through 48 weeks of treatment. Methods TMB-301 was an open-label study investigating the antiviral activity and safety of IBA plus OBR in highly treatment-experienced patients with MDR HIV-1. Patients received an intravenous loading dose of 2,000mg followed by 800mg doses every 2 weeks for 24 weeks. 7 days after loading dose, an OBR was added with at least 1 additional sensitive agent throughout the study. Following completion of the 24-week TMB-301 study, patients continued to receive IBA at 800mg every 2 weeks under TMB-311 for up to 48 weeks. Safety and efficacy were assessed until 48 weeks. Results A total of 31 patients enrolled in TMB-301 completed the 24-week treatment period. Of 31 patients, 27 entered study TMB-311. These patients were highly resistant patients - 59% and 33% of patients had exhausted ≥3 and ≥4 ARV classes, respectively, and 7% of patients had HIV-1 resistant to all approved ARVs. IBA plus OBR was well tolerated. Of the 27 patients, 24 (89%) continued to receive treatment until Week 48. The three patients discontinued early due to non IBA-related reasons. No new or unexpected safety concerns emerged between Week 24 and 48. The potent suppression of viremia observed Week 24 was sustained through Week 48. Median viral load (VL) reduction from BL was 2.5 log10 at both Week 24 and 48. Of 27 patients (59%) 16 had VL Conclusion IBA plus OBR continued to achieve high rates of virologic suppression through Week 48. The results support the durable efficacy and long-term safety of IBA in highly treatment-experienced MDR patients and offer a valuable treatment option for patients. Disclosures B. Emu, TaiMed Biologics: Employee and Shareholder, Salary; P. N. Kumar, TaiMed: Advisory Board and Investigator, Consulting fee and Grant recipient; G. Richmond, TaiMed: Investigator, Research support; S. Weinheimer, TaiMed: Employee, Salary; C. Marsolais, TaiMed: Commercial partner, Salary and Salary from Theratechnologies, commercial partner; S. Lewis, TaiMed: Employee, Salary and Salary from Theratechnologies, commercial partner more...
- Published
- 2017
44. Relationship between T Cell Activation and CD4+T Cell Count in HIV‐Seropositive Individuals with Undetectable Plasma HIV RNA Levels in the Absence of Therapy
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Joseph M. McCune, Melissa R. Krone, Jeffrey N. Martin, Kimberly Page-Shafer, Jason M. Brenchley, Daniel C. Douek, Brinda Emu, Elizabeth Sinclair, Michelle E. Roland, Steven G. Deeks, Priscilla Y. Hsue, Peter W. Hunt, and Harry Lampiris more...
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Adult ,Male ,T-Lymphocytes ,T cell ,HIV Infections ,CD38 ,Lymphocyte Activation ,Article ,Cohort Studies ,Immune system ,Acquired immunodeficiency syndrome (AIDS) ,HIV Seropositivity ,medicine ,Humans ,Immunology and Allergy ,Viremia ,Immunodeficiency ,biology ,Middle Aged ,biology.organism_classification ,medicine.disease ,Virology ,CD4 Lymphocyte Count ,Infectious Diseases ,medicine.anatomical_structure ,Viral replication ,Lentivirus ,Immunology ,HIV-1 ,RNA, Viral ,Female ,CD8 - Abstract
Fewer than 1% of chronically HIV-infected individuals are capable of maintaining clinically undetectable plasma HIV RNA levels (
- Published
- 2008
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45. Loss of T cell responses following long-term cryopreservation
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Jeffery N Martin, Qi Xuan Tan, Rachel E. Owen, Frederick Hecht, Jeffery M. Harris, Mark A. Jacobson, John W. Heitman, Joseph M. McCune, Dale F. Hirschkorn, Brian Custer, Philip J. Norris, Elizabeth Sinclair, Steven G. Deeks, C. Lorrie Epling, and Brinda Emu more...
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Male ,Time Factors ,T-Lymphocytes ,medicine.medical_treatment ,T cell ,Immunology ,Cytomegalovirus ,Apoptosis ,HIV Infections ,Biology ,Peripheral blood mononuclear cell ,Article ,Cryopreservation ,Cell Line ,Interleukin 21 ,medicine ,Humans ,Immunology and Allergy ,Cytotoxic T cell ,Cells, Cultured ,Cell Line, Transformed ,B-Lymphocytes ,HIV ,T lymphocyte ,Coculture Techniques ,Cytokine ,medicine.anatomical_structure ,Acute Disease ,Chronic Disease ,Cytomegalovirus Infections ,CD8 - Abstract
Although cryopreservation of peripheral blood mononuclear cells (PBMC) is a commonly used technique, the degree to which it affects subsequent functional studies has not been well defined. Here we demonstrate that long-term cryopreservation has detrimental effects on T cell IFN-gamma responses in human immunodeficiency virus (HIV) infected individuals. Long-term cryopreservation caused marked decreases in CD4(+) T cell responses to whole proteins (HIV p55 and cytomegalovirus (CMV) lysate) and HIV peptides, and more limited decreases in CD8(+) T cell responses to whole proteins. These losses were more apparent in cells stored for greater than one year compared to less than six months. CD8(+) T cell responses to peptides and peptide pools were well preserved. Loss of both CD4(+) and CD8(+) T cell responses to CMV peptide pools were minimal in HIV-negative individuals. Addition of exogenous antigen presenting cells (APC) did not restore CD4(+) T cell responses to peptide stimulation and partially restored T cell IFN-gamma responses to p55 protein. Overnight resting of thawed cells did not restore T cell IFN-gamma responses to peptide or whole protein stimulation. A selective loss of phenotypically defined effector cells did not explain the decrement of responses, although cryopreservation did increase CD4(+) T cell apoptosis, possibly contributing to the loss of responses. These data suggest that the impact of cryopreservation should be carefully considered in future vaccine and pathogenesis studies. In HIV-infected individuals short-term cryopreservation may be acceptable for measuring CD4(+) and CD8(+) T cell responses. Long-term cryopreservation, however, may lead to the loss of CD4(+) T cell responses and mild skewing of T cell phenotypic marker expression. more...
- Published
- 2007
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46. Phenotypic, Functional, and Kinetic Parameters Associated with Apparent T-Cell Control of Human Immunodeficiency Virus Replication in Individuals with and without Antiretroviral Treatment
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Elizabeth Sinclair, Priscilla Y. Hsue, Steven G. Deeks, Brinda Emu, Douglas F. Nixon, Walter J. Moretto, David Favre, Rebecca Hoh, Joseph M. McCune, and Jeffrey N. Martin
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Adult ,CD4-Positive T-Lymphocytes ,Interleukin 2 ,Anti-HIV Agents ,T-Lymphocytes ,T cell ,Immunology ,HIV Infections ,Viremia ,CD8-Positive T-Lymphocytes ,Biology ,Lymphocyte Activation ,Microbiology ,Interferon-gamma ,Immune system ,Antigens, CD ,Virology ,medicine ,Humans ,Interferon gamma ,virus diseases ,HIV ,CD28 ,T lymphocyte ,Viral Load ,medicine.disease ,CD4 Lymphocyte Count ,Kinetics ,Phenotype ,medicine.anatomical_structure ,Insect Science ,Pathogenesis and Immunity ,Interleukin-2 ,RNA, Viral ,CD8 ,medicine.drug - Abstract
The human immunodeficiency virus (HIV)-mediated immune response may be beneficial or harmful, depending on the balance between expansion of HIV-specific T cells and the level of generalized immune activation. The current study utilizes multicolor cytokine flow cytometry to study HIV-specific T cells and T-cell activation in 179 chronically infected individuals at various stages of HIV disease, including those with low-level viremia in the absence of therapy (“controllers”), low-level drug-resistant viremia in the presence of therapy (partial controllers on antiretroviral therapy [PCAT]), and high-level viremia (“noncontrollers”). Compared to noncontrollers, controllers exhibited higher frequencies of HIV-specific interleukin-2-positive gamma interferon-positive (IL-2 + IFN-γ + ) CD4 + T cells. The presence of HIV-specific CD4 + IL-2 + T cells was associated with low levels of proliferating T cells within the less-differentiated T-cell subpopulations (defined by CD45RA, CCR7, CD27, and CD28). Despite prior history of progressive disease, PCAT patients exhibited many immunologic characteristics seen in controllers, including high frequencies of IL-2 + IFN-γ + CD4 + T cells. Measures of immune activation were lower in all CD8 + T-cell subsets in controllers and PCAT compared to noncontrollers. Thus, control of HIV replication is associated with high levels of HIV-specific IL-2 + and IFN-γ + CD4 + T cells and low levels of T-cell activation. This immunologic state is one where the host responds to HIV by expanding but not exhausting HIV-specific T cells while maintaining a relatively quiescent immune system. Despite a history of advanced HIV disease, a subset of individuals with multidrug-resistant HIV exhibit an immunologic profile comparable to that of controllers, suggesting that functional immunity can be reconstituted with partially suppressive highly active antiretroviral therapy. more...
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- 2005
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47. Answer to December 2017 Photo Quiz
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Raffaele Bernardo, Jaimie P. Meyer, Benjamin A. Rodwin, Amir M. Mohareb, Brinda Emu, Perry Tiberio, Shoshana Streiter, and Onyema Ogbuagu
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Microbiology (medical) ,food.ingredient ,030231 tropical medicine ,Photo Quiz ,Biology ,Mansonelliasis ,Mansonella ,biology.organism_classification ,medicine.disease ,Culicoides ,Virology ,Microfilaria ,Peripheral blood ,03 medical and health sciences ,0302 clinical medicine ,food ,parasitic diseases ,medicine ,Eosinophilia ,Mansonella perstans ,030212 general & internal medicine ,medicine.symptom - Abstract
Answer: Mansonella perstans. A Wright-Giemsa-stained peripheral blood smear demonstrated an unsheathed microfilaria with nuclei extending to the tip of a blunt tail, characteristic of Mansonella perstans, measuring approximately 100 μm. M. perstans is transmitted by the Culicoides fly, endemic to more...
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- 2017
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48. Impact of illicit opioid use on T cell subsets among HIV-infected adults
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Evgeny Krupitsky, Elena Blokhina, Dmitry Lioznov, E. Jennifer Edelman, Debbie M. Cheng, Matthew S. Freiberg, Natalia Gnatienko, Margaret F. Doyle, Brinda Emu, Kaku So-Armah, Sharon M. Coleman, Carly Bridden, and Jeffrey H. Samet more...
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Male ,0301 basic medicine ,lcsh:Medicine ,HIV Infections ,Signal transduction ,Pharmacology ,Memory T cells ,White Blood Cells ,Cognition ,Learning and Memory ,0302 clinical medicine ,T-Lymphocyte Subsets ,Animal Cells ,Medicine and Health Sciences ,Cytotoxic T cell ,030212 general & internal medicine ,lcsh:Science ,Analgesics ,Multidisciplinary ,T Cells ,Drugs ,CD28 ,HIV diagnosis and management ,3. Good health ,medicine.anatomical_structure ,Cohort ,Female ,HIV clinical manifestations ,Cellular Types ,Coreceptors ,Research Article ,medicine.drug ,Adult ,Senescence ,medicine.medical_specialty ,Immune Cells ,T cell ,Immunology ,Cytotoxic T cells ,03 medical and health sciences ,Immune system ,Memory ,Internal medicine ,medicine ,Humans ,Pain Management ,Blood Cells ,business.industry ,lcsh:R ,Biology and Life Sciences ,CD coreceptors ,Cell Biology ,Opioid-Related Disorders ,Diagnostic medicine ,Opioids ,030104 developmental biology ,Opioid ,Cognitive Science ,lcsh:Q ,business ,CD8 ,Neuroscience - Abstract
Objectives Opioids have immunosuppressive properties, yet opioid effects on T cell abnormalities consistent with the immune risk phenotype among HIV-infected individuals are understudied. Methods To assess associations between illicit opioid use and T cell characteristics (CD4/CD8 ratio, memory profiles based on CD45RO and CD28 expression, and senescence based on CD57 expression), we conducted an exploratory cross-sectional analysis of Russia ARCH, a cohort of antiretroviral therapy (ART)-naïve HIV-infected individuals recruited 11/2012 to 10/2014 in St. Petersburg, Russia. The main independent variable was past 30 day illicit opioid use (yes vs. no). Secondary analyses evaluated none (0 days), intermittent (1 to 7 days), and persistent (8 to 30 days) opioid use. Outcomes were determined with flow cytometry. Analyses were conducted using linear regression models. Results Among 186 participants, 38% reported any illicit opioid use (18% intermittent and 20% persistent). Any illicit opioid use was not significantly associated with T cell characteristics. Intermittent opioid use appeared to be associated with decreased memory CD8+ T cells proportion (CD45RO+CD45RA- CD8+ T cells: adjusted mean difference [AMD] [95% CI] = -6.15 [-11.50, -0.79], p = 0.02) and borderline significant increased senescent T cells (%CD57+ of total CD28-CD8+ T cells (AMD [95% CI] = 7.70 [-0.06, 15.46], p = 0.05). Conclusions Among ART-naïve HIV-infected Russians, any illicit opioid use was not significantly associated with T cell abnormalities although intermittent illicit opioid use may be associated with CD8 T cell abnormalities. Longitudinal studies are warranted to confirm these findings given increased risk of infections and comorbidities seen among HIV-infected individuals with illicit opioid use. more...
- Published
- 2017
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49. Composition and function of T cell subpopulations are slow to change despite effective antiretroviral treatment of HIV disease
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Rebecca Hoh, Melissa R. Krone, Steven G. Deeks, Walter J. Moretto, Joseph M. McCune, Jeffrey N. Martin, Douglas F. Nixon, and Brinda Emu
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CD4-Positive T-Lymphocytes ,Male ,Viral Diseases ,Human immunodeficiency virus (HIV) ,Gene Expression ,lcsh:Medicine ,HIV Infections ,Adaptive Immunity ,CD8-Positive T-Lymphocytes ,medicine.disease_cause ,Lymphocyte Activation ,T-Lymphocyte Subsets ,Cytotoxic T cell ,Prospective Studies ,lcsh:Science ,Multidisciplinary ,T Cells ,Aging and Immunity ,Middle Aged ,Viral Load ,3. Good health ,medicine.anatomical_structure ,Infectious Diseases ,Disease Progression ,Cytokines ,Medicine ,Female ,Viral load ,Research Article ,Adult ,Anti-HIV Agents ,T cell ,Immune Cells ,Immunology ,Biology ,Immune Deficiency ,Immune system ,Antigens, CD ,medicine ,Antiretroviral treatment ,Humans ,lcsh:R ,Immunity ,HIV ,Antiretroviral therapy ,CD4 Lymphocyte Count ,Immune System ,HIV-1 ,Clinical Immunology ,lcsh:Q ,Function (biology) - Abstract
The ability to reconstitute a normal immune system with antiretroviral therapy in the setting of HIV infection remains uncertain. This study aimed to characterize quantitative and qualitative aspects of various T cell subpopulations that do not improve despite effective ART. CD4∶CD8 ratio was evaluated in HIV-infected subjects with viral loads >10,000 copies/µl (“non-controllers”, n = 42), those with undetectable viral loads on ART (“ART-suppressed”, n = 53), and HIV-uninfected subjects (n = 22). In addition, T cell phenotype and function were examined in 25 non-controllers, 18 ART-suppressed, and 7 HIV-uninfected subjects. CD4∶CD8 ratio in non-controllers, ART-suppressed, and HIV-uninfected subjects was 0.25, 0.48, and 1.95 respectively (P more...
- Published
- 2014
50. A low T regulatory cell response may contribute to both viral control and generalized immune activation in HIV controllers
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Alan L. Landay, Cicely Brooks, Elizabeth Sinclair, Philip J. Norris, Joseph M. McCune, Jeffrey N. Martin, Hiroyu Hatano, Michael P. Busch, Peter W. Hunt, Jeffrey Martinson, Brinda Emu, Steven G. Deeks, and Ostrowski, Mario more...
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T-Lymphocytes ,Cytomegalovirus ,lcsh:Medicine ,HIV Infections ,T-Cell Antigen Receptor Specificity ,CD38 ,Lymphocyte Activation ,T-Lymphocytes, Regulatory ,0302 clinical medicine ,Models ,2.1 Biological and endogenous factors ,Cytotoxic T cell ,030212 general & internal medicine ,IL-2 receptor ,Aetiology ,lcsh:Science ,0303 health sciences ,Multidisciplinary ,virus diseases ,Acquired immune system ,Regulatory ,3. Good health ,Infectious Diseases ,medicine.anatomical_structure ,Immunological ,HIV/AIDS ,Medicine ,Infectious diseases ,Infection ,Research Article ,General Science & Technology ,T cell ,Immunology ,Retrovirology and HIV immunopathogenesis ,Viral diseases ,Biology ,Immune Activation ,03 medical and health sciences ,Immune system ,Clinical Research ,medicine ,Viremia ,Interleukin-7 receptor ,030304 developmental biology ,Inflammatory and immune system ,lcsh:R ,Immunity ,Models, Immunological ,Immunoregulation ,HIV ,Good Health and Well Being ,Case-Control Studies ,Immunization ,lcsh:Q ,CD8 - Abstract
HIV-infected individuals maintaining undetectable viremia in the absence of therapy (HIV controllers) often maintain high HIV-specific T cell responses, which has spurred the development of vaccines eliciting HIV-specific T cell responses. However, controllers also often have abnormally high T cell activation levels, potentially contributing to T cell dysfunction, CD4+ T cell depletion, and non-AIDS morbidity. We hypothesized that a weak T regulatory cell (Treg) response might contribute to the control of viral replication in HIV controllers, but might also contribute to generalized immune activation, contributing to CD4+ T cell loss. To address these hypotheses, we measured frequencies of activated (CD38+ HLA-DR+), regulatory (CD4+CD25+CD127(dim)), HIV-specific, and CMV-specific T cells among HIV controllers and 3 control populations: HIV-infected individuals with treatment-mediated viral suppression (ART-suppressed), untreated HIV-infected "non-controllers" with high levels of viremia, and HIV-uninfected individuals. Despite abnormally high T cell activation levels, controllers had lower Treg frequencies than HIV-uninfected controls (P = 0.014). Supporting the propensity for an unusually low Treg response to viral infection in HIV controllers, we observed unusually high CMV-specific CD4+ T cell frequencies and a strong correlation between HIV-specific CD4+ T cell responses and generalized CD8+ T cell activation levels in HIV controllers (P ≤ 0.001). These data support a model in which low frequencies of Tregs in HIV controllers may contribute to an effective adaptive immune response, but may also contribute to generalized immune activation, potentially contributing to CD4 depletion. more...
- Published
- 2011
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