166 results on '"Otto O"'
Search Results
2. [The transition period of the medical profession--from where the support?].
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Haahtela T, Lindberg O, and Mustajoki P
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- Clinical Competence, Humans, Social Change, Societies, Medical organization & administration, Societies, Medical trends, Delivery of Health Care trends, Education, Medical standards, Medicine trends, Physicians psychology
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- 2003
3. Predominantly defective CD8+ T cell immunity to SARS-CoV-2 mRNA vaccination in lung transplant recipients
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Ellie Taus, Michael Y. Shino, F. Javier Ibarrondo, Mary Ann Hausner, Christian Hofmann, and Otto O. Yang
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SARS-CoV-2 ,COVID-19 mRNA vaccine ,Solid organ transplantation ,Lung transplantation ,Cellular immunity ,Medicine - Abstract
Abstract Background Although mRNA vaccines have overall efficacy preventing morbidity/mortality from SARS-CoV-2 infection, immunocompromised persons remain at risk. Antibodies mostly prevent early symptomatic infection, but cellular immunity, particularly the virus-specific CD8+ T cell response, is protective against disease. Defects in T cell responses to vaccination have not been well characterized in immunocompromised hosts; persons with lung transplantation are particularly vulnerable to vaccine failure with severe illness. Methods Comparison groups included persons with lung transplantation and no history of COVID-19 (21 and 19 persons after initial mRNA vaccination and a third booster vaccination respectively), 8 lung transplantation participants recovered from COVID-19, and 22 non-immunocompromised healthy control individuals after initial mRNA vaccination (without history of COVID-19). Anti-spike T cell responses were assayed by stimulating peripheral blood mononuclear cells (PBMCs) with pooled small overlapping peptides spanning the SARS-CoV-2 spike protein, followed by intracellular cytokine staining (ICS) and flow cytometry for release of cytokines in response to stimulation, including negative controls (no peptide stimulation) and positive controls (phorbol myristate acetate [PMA] and ionomycin stimulation). To evaluate for low frequency memory responses, PBMCs were cultured in the presence of the mRNA-1273 vaccine for 14 days before this evaluation. Results Ionophore stimulation of PBMCs revealed a less inflammatory milieu in terms of interleukin (IL)-2, IL-4, and IL-10 profiling in lung transplantation individuals, reflecting the effect of immunosuppressive treatments. Similar to what we previously reported in healthy vaccinees, spike-specific responses in lung transplantation recipients were undetectable (
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- 2023
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4. Early SARS-CoV-2 dynamics and immune responses in unvaccinated participants of an intensely sampled longitudinal surveillance study
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Manjula Gunawardana, Simon Webster, Sofia Rivera, John M. Cortez, Jessica Breslin, Cristian Pinales, Christopher Buser, F. Javier Ibarrondo, Otto O. Yang, Michael Bobardt, Philippe A. Gallay, Amy P. Adler, Christina M. Ramirez, Peter A. Anton, and Marc M. Baum
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Medicine - Abstract
Gunawardana et al. monitor the viral load, inflammatory biomarkers and antibody response long-term in people who developed COVID-19. Early viral replication is rapid, providing a narrow window between exposure and viral shedding.
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- 2022
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5. Autophagy inducer rapamycin treatment reduces IFN-I–mediated Inflammation and improves anti–HIV-1 T cell response in vivo
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Wenli Mu, Valerie Rezek, Heather Martin, Mayra A. Carrillo, Shallu Tomer, Philip Hamid, Miguel A. Lizarraga, Tristan D. Tibbe, Otto O. Yang, Beth D. Jamieson, Scott G. Kitchen, and Anjie Zhen
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AIDS/HIV ,Inflammation ,Medicine - Abstract
A hallmark of HIV-1 infection is chronic inflammation, even in patients treated with antiretroviral therapy (ART). Chronic inflammation drives HIV-1 pathogenesis, leading to loss of CD4+ T cells and exhaustion of antiviral immunity. Therefore, strategies to safely reduce systematic inflammation are needed to halt disease progression and restore defective immune responses. Autophagy is a cellular mechanism for disposal of damaged organelles and elimination of intracellular pathogens. Autophagy is pivotal for energy homeostasis and plays critical roles in regulating immunity. However, how it regulates inflammation and antiviral T cell responses during HIV infection is unclear. Here, we demonstrate that autophagy is directly linked to IFN-I signaling, which is a key driver of immune activation and T cell exhaustion during chronic HIV infection. Impairment of autophagy leads to spontaneous IFN-I signaling, and autophagy induction reduces IFN-I signaling in monocytic cells. Importantly, in HIV-1–infected humanized mice, autophagy inducer rapamycin treatment significantly reduced persistent IFN-I–mediated inflammation and improved antiviral T cell responses. Cotreatment of rapamycin with ART led to significantly reduced viral rebound after ART withdrawal. Taken together, our data suggest that therapeutically targeting autophagy is a promising approach to treat persistent inflammation and improve immune control of HIV replication.
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- 2022
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6. Humoral responses to SARS-CoV-2 mRNA vaccines: Role of past infection
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Ashley N. Gray, Rachel Martin-Blais, Nicole H. Tobin, Yan Wang, Sarah L. Brooker, Fan Li, Adva Gadoth, Julie Elliott, Emmanuelle Faure-Kumar, Megan Halbrook, Christian Hofmann, Saman Kashani, Clayton Kazan, Otto O. Yang, Jennifer A. Fulcher, Kathie Grovit-Ferbas, Anne W. Rimoin, and Grace M. Aldrovandi
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Medicine ,Science - Abstract
Two mRNA vaccines (BNT162b2 and mRNA-1273) against severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) are globally authorized as a two-dose regimen. Understanding the magnitude and duration of protective immune responses is vital to curbing the pandemic. We enrolled 461 high-risk health services workers at the University of California, Los Angeles (UCLA) and first responders in the Los Angeles County Fire Department (LACoFD) to assess the humoral responses in previously infected (PI) and infection naïve (NPI) individuals to mRNA-based vaccines (BNT162b2/Pfizer- BioNTech or mRNA-1273/Moderna). A chemiluminescent microparticle immunoassay was used to detect antibodies against SARS-CoV-2 Spike in vaccinees prior to (n = 21) and following each vaccine dose (n = 246 following dose 1 and n = 315 following dose 2), and at days 31–60 (n = 110) and 61–90 (n = 190) following completion of the 2-dose series. Both vaccines induced robust antibody responses in all immunocompetent individuals. Previously infected individuals achieved higher median peak titers (p = 0.002) and had a slower rate of decay (p = 0.047) than infection-naïve individuals. mRNA-1273 vaccinated infection-naïve individuals demonstrated modestly higher titers following each dose (p = 0.005 and p = 0.029, respectively) and slower rates of antibody decay (p = 0.003) than those who received BNT162b2. A subset of previously infected individuals (25%) required both doses in order to reach peak antibody titers. The biologic significance of the differences between previously infected individuals and between the mRNA-1273 and BNT162b2 vaccines remains uncertain, but may have important implications for booster strategies.
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- 2021
7. Distinct aging profiles of CD8+ T cells in blood versus gastrointestinal mucosal compartments.
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Jeffrey Dock, Christina M Ramirez, Lance Hultin, Mary Ann Hausner, Patricia Hultin, Julie Elliott, Otto O Yang, Peter A Anton, Beth D Jamieson, and Rita B Effros
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Medicine ,Science - Abstract
A hallmark of human immunosenescence is the accumulation of late-differentiated memory CD8+ T cells with features of replicative senescence, such as inability to proliferate, absence of CD28 expression, shortened telomeres, loss of telomerase activity, enhanced activation, and increased secretion of inflammatory cytokines. Importantly, oligoclonal expansions of these cells are associated with increased morbidity and mortality risk in elderly humans. Currently, most information on the adaptive immune system is derived from studies using peripheral blood, which contains approximately only 2% of total body lymphocytes. However, most lymphocytes reside in tissues. It is not clear how representative blood changes are of the total immune status. This is especially relevant with regard to the human gastrointestinal tract (GALT), a major reservoir of total body lymphocytes (approximately 60%) and an anatomical region of high antigenic exposure. To assess how peripheral blood T cells relate to those in other locations, we compare CD8+ T cells from peripheral blood and the GALT, specifically rectosigmoid colon, in young/middle age, healthy donors, focusing on phenotypic and functional alterations previously linked to senescence in peripheral blood. Overall, our results indicate that gut CD8+ T cells show profiles suggestive of greater differentiation and activation than those in peripheral blood. Specifically, compared to blood from the same individual, the gut contains significantly greater proportions of CD8+ T cells that are CD45RA- (memory), CD28-, CD45RA-CD28+ (early memory), CD45RA-CD28- (late memory), CD25-, HLA-DR+CD38+ (activated) and Ki-67+ (proliferating); ex vivo CD3+ telomerase activity levels are greater in the gut as well. However, gut CD8+ T cells may not necessarily be more senescent, since they expressed significantly lower levels of CD57 and PD-1 on CD45RO+ memory cells, and had in vitro proliferative dynamics similar to that of blood cells. Compartment-specific age-effects in this cohort were evident as well. Blood cells showed a significant increase with age in proportion of HLA-DR+38+, Ki-67+ and CD25+ CD8+ T cells; and an increase in total CD3+ ex-vivo telomerase activity that approached significance. By contrast, the only age-effect seen in the gut was a significant increase in CD45RA- (memory) and concurrent decrease in CD45RA+CD28+ (naïve) CD8+ T cells. Overall, these results indicate dynamics of peripheral blood immune senescence may not hold true in the gut mucosa, underscoring the importance for further study of this immunologically important tissue in evaluating the human immune system, especially in the context of chronic disease and aging.
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- 2017
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8. Clonal CD8+ T Cell Persistence and Variable Gene Usage Bias in a Human Transplanted Hand.
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Joseph Y Kim, Arumugam Balamurugan, Kodi Azari, Christian Hofmann, Hwee L Ng, Elaine F Reed, Suzanne McDiarmid, and Otto O Yang
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Medicine ,Science - Abstract
Immune prophylaxis and treatment of transplanted tissue rejection act indiscriminately, risking serious infections and malignancies. Although animal data suggest that cellular immune responses causing rejection may be rather narrow and predictable based on genetic background, there are only limited data regarding the clonal breadth of anti-donor responses in humans after allogeneic organ transplantation. We evaluated the graft-infiltrating CD8+ T lymphocytes in skin punch biopsies of a transplanted hand over 178 days. Profiling of T cell receptor (TCR) variable gene usage and size distribution of the infiltrating cells revealed marked skewing of the TCR repertoire indicating oligoclonality, but relatively normal distributions in the blood. Although sampling limitation prevented complete assessment of the TCR repertoire, sequencing further identified 11 TCR clonal expansions that persisted through varying degrees of clinical rejection and immunosuppressive therapy. These 11 clones were limited to three TCR beta chain variable (BV) gene families. Overall, these data indicate significant oligoclonality and likely restricted BV gene usage of alloreactive CD8+ T lymphocytes, and suggest that changes in rejection status are more due to varying regulation of their activity or number rather than shifts in the clonal populations in the transplanted organ. Given that controlled animal models produce predictable BV usage in T lymphocytes mediating rejection, understanding the determinants of TCR gene usage associated with rejection in humans may have application in specifically targeted immunotherapy.
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- 2015
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9. T lymphocyte density and distribution in human colorectal mucosa, and inefficiency of current cell isolation protocols.
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Gloria Cuevas Preza, Otto O Yang, Julie Elliott, Peter A Anton, and Maria T Ochoa
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Medicine ,Science - Abstract
Mucosal tissues are critical immune effector sites containing complex populations of leukocytes in a tissue microenvironment that remains incompletely understood. We identify and quantify in human distal colorectal tissue absolute mucosal CD3+ lymphocytes, including CD4+ and CD8+ subsets, by direct visualization using immunohistochemistry (IHC), immunofluorescence (IF), and an automated counting protocol (r2=0.90). Sigmoid and rectal mucosal tissues are both densely packed with T lymphocytes in the mucosal compartment. Both compartments had similar densities of CD3+ T lymphocytes with 37,400 ± 2,801 cells/mm3 and 33,700 ± 4,324 cell/mm3, respectively. Sigmoid mucosa contained 57% CD3+CD4+ and 40% CD3+CD8+ T lymphocytes which calculates to 21,300 ± 1,476/mm3 and 15,000 ± 275/mm3 T lymphocytes, respectively. Rectal mucosa had 57% CD3+CD4+ and 42% CD3+CD8+ or 21,577 ± 332, and 17,090 ± 1,206 cells/mm3, respectively. By comparison, sigmoid mucosal biopsies subjected to conventional collagenase digestion, mononuclear cell (MMC) isolation and staining for flow cytometry yielded 4,549 ± 381/mm3 and 2,708 ± 245/mm3 CD4+ and CD8+ T lymphocytes. These data suggest only ~20.7% recovery compared to IHC results for these markers. Further studies will determine if this reflects a selective bias in only CD3+, CD4+ and CD8+ T cells or can be generalized to all flow-analyzed cells from mucosal tissues for phenotyping and functional testing.
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- 2015
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10. Correction: Clonal CD8+ T Cell Persistence and Variable Gene Usage Bias in a Human Transplanted Hand.
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Joseph Y Kim, Arumugam Balamurugan, Kodi Azari, Christian Hofmann, Hwee L Ng, Elaine F Reed, Suzanne McDiarmid, and Otto O Yang
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Medicine ,Science - Published
- 2015
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11. A high throughput biochemical fluorometric method for measuring lipid peroxidation in HDL.
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Theodoros Kelesidis, Christian K Roberts, Diana Huynh, Otoniel Martínez-Maza, Judith S Currier, Srinivasa T Reddy, and Otto O Yang
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Medicine ,Science - Abstract
Current cell-based assays for determining the functional properties of high-density lipoproteins (HDL) have limitations. We report here the development of a new, robust fluorometric cell-free biochemical assay that measures HDL lipid peroxidation (HDLox) based on the oxidation of the fluorochrome Amplex Red. HDLox correlated with previously validated cell-based (r = 0.47, p
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- 2014
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12. Differential blood and mucosal immune responses against an HIV-1 vaccine administered via inguinal or deltoid injection.
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Otto O Yang, F Javier Ibarrondo, Charles Price, Lance E Hultin, Julie Elliott, Patricia M Hultin, Roger Shih, Mary Ann Hausner, Hwee L Ng, Jennifer Hoffman, Beth D Jamieson, and Peter A Anton
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Medicine ,Science - Abstract
Mucosal immunity is central to sexual transmission and overall pathogenesis of HIV-1 infection, but the ability of vaccines to induce immune responses in mucosal tissue compartments is poorly defined. Because macaque vaccine studies suggest that inguinal (versus limb) vaccination may better target sexually-exposed mucosa, we performed a randomized, double-blinded, placebo-controlled Phase I trial in HIV-1-uninfected volunteers, using the recombinant Canarypox (CP) vaccine vCP205 delivered by different routes. 12 persons received vaccine and 6 received placebo, divided evenly between deltoid-intramuscular (deltoid-IM) or inguinal-subcutaneous (inguinal-SC) injection routes. The most significant safety events were injection site reactions (Grade 3) in one inguinal vaccinee. CP-specific antibodies were detected in the blood of all 12 vaccinees by Day 24, while HIV-1-specific antibodies were observed in the blood and gut mucosa of 1/9 and 4/9 evaluated vaccinees respectively, with gut antibodies appearing earlier in inguinal vaccinees (24-180 versus 180-365 days). HIV-1-specific CD8(+) T lymphocytes (CTLs) were observed in 7/12 vaccinees, and blood and gut targeting were distinct. Within blood, both deltoid and inguinal responders had detectable CTL responses by 17-24 days; inguinal responders had early responses (within 10 days) while deltoid responders had later responses (24-180 days) in gut mucosa. Our results demonstrate relative safety of inguinal vaccination and qualitative or quantitative compartmentalization of immune responses between blood and gut mucosa, and highlight the importance of not only evaluating early blood responses to HIV-1 vaccines but also mucosal responses over time.ClinicalTrials.gov NCT00076817.
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- 2014
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13. HIV-1 quasispecies delineation by tag linkage deep sequencing.
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Nicholas C Wu, Justin De La Cruz, Laith Q Al-Mawsawi, C Anders Olson, Hangfei Qi, Harding H Luan, Nguyen Nguyen, Yushen Du, Shuai Le, Ting-Ting Wu, Xinmin Li, Martha J Lewis, Otto O Yang, and Ren Sun
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Medicine ,Science - Abstract
Trade-offs between throughput, read length, and error rates in high-throughput sequencing limit certain applications such as monitoring viral quasispecies. Here, we describe a molecular-based tag linkage method that allows assemblage of short sequence reads into long DNA fragments. It enables haplotype phasing with high accuracy and sensitivity to interrogate individual viral sequences in a quasispecies. This approach is demonstrated to deduce ∼ 2000 unique 1.3 kb viral sequences from HIV-1 quasispecies in vivo and after passaging ex vivo with a detection limit of ∼ 0.005% to ∼ 0.001%. Reproducibility of the method is validated quantitatively and qualitatively by a technical replicate. This approach can improve monitoring of the genetic architecture and evolution dynamics in any quasispecies population.
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- 2014
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14. A stochastic multi-scale model of HIV-1 transmission for decision-making: application to a MSM population.
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Lilit Yeghiazarian, William G Cumberland, and Otto O Yang
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Medicine ,Science - Abstract
BackgroundIn the absence of an effective vaccine against HIV-1, the scientific community is presented with the challenge of developing alternative methods to curb its spread. Due to the complexity of the disease, however, our ability to predict the impact of various prevention and treatment strategies is limited. While ART has been widely accepted as the gold standard of modern care, its timing is debated.ObjectivesTo evaluate the impact of medical interventions at the level of individuals on the spread of infection across the whole population. Specifically, we investigate the impact of ART initiation timing on HIV-1 spread in an MSM (Men who have Sex with Men) population.Design and methodsA stochastic multi-scale model of HIV-1 transmission that integrates within a single framework the in-host cellular dynamics and their outcomes, patient health states, and sexual contact networks. The model captures disease state and progression within individuals, and allows for simulation of therapeutic strategies.ResultsEarly ART initiation may substantially affect disease spread through a population.ConclusionsOur model provides a multi-scale, systems-based approach to evaluate the broader implications of therapeutic strategies.
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- 2013
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15. HIV-1 Nef sequence and functional compartmentalization in the gut is not due to differential cytotoxic T lymphocyte selective pressure.
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Martha J Lewis, Patricia Frohnen, F Javier Ibarrondo, Diane Reed, Varun Iyer, Hwee L Ng, Julie Elliott, Otto O Yang, and Peter Anton
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Medicine ,Science - Abstract
The gut is the largest lymphoid organ in the body and a site of active HIV-1 replication and immune surveillance. The gut is a reservoir of persistent infection in some individuals with fully suppressed plasma viremia on combination antiretroviral therapy (cART) although the cause of this persistence is unknown. The HIV-1 accessory protein Nef contributes to persistence through multiple functions including immune evasion and increasing infectivity. Previous studies showed that Nef's function is shaped by cytotoxic T lymphocyte (CTL) responses and that there are distinct populations of Nef within tissue compartments. We asked whether Nef's sequence and/or function are compartmentalized in the gut and how compartmentalization relates to local CTL immune responses. Primary nef quasispecies from paired plasma and sigmoid colon biopsies from chronically infected subjects not on therapy were sequenced and cloned into Env(-) Vpu(-) pseudotyped reporter viruses. CTL responses were mapped by IFN-γ ELISpot using expanded CD8+ cells from blood and gut with pools of overlapping peptides covering the entire HIV proteome. CD4 and MHC Class I Nef-mediated downregulation was measured by flow cytometry. Multiple tests indicated compartmentalization of nef sequences in 5 of 8 subjects. There was also compartmentalization of function with MHC Class I downregulation relatively well preserved, but significant loss of CD4 downregulation specifically by gut quasispecies in 5 of 7 subjects. There was no compartmentalization of CTL responses in 6 of 8 subjects, and the selective pressure on quasispecies correlated with the magnitude CTL response regardless of location. These results demonstrate that Nef adapts via diverse pathways to local selective pressures within gut mucosa, which may be predominated by factors other than CTL responses such as target cell availability. The finding of a functionally distinct population within gut mucosa offers some insight into how HIV-1 may persist in the gut despite fully suppressed plasma viremia on cART.
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- 2013
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16. Natural killer T cells in advanced melanoma patients treated with tremelimumab.
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F Javier Ibarrondo, Otto O Yang, Thinle Chodon, Earl Avramis, Yohan Lee, Hooman Sazegar, Jason Jalil, Bartosz Chmielowski, Richard C Koya, Ingrid Schmid, Jesus Gomez-Navarro, Beth D Jamieson, Antoni Ribas, and Begoña Comin-Anduix
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Medicine ,Science - Abstract
A significant barrier to effective immune clearance of cancer is loss of antitumor cytotoxic T cell activity. Antibodies to block pro-apoptotic/downmodulatory signals to T cells are currently being tested. Because invariant natural killer T cells (iNKT) can regulate the balance of Th1/Th2 cellular immune responses, we characterized the frequencies of circulating iNKT cell subsets in 21 patients with melanoma who received the anti-CTLA4 monoclonal antibody tremelimumab alone and 8 patients who received the antibody in combination with MART-126-35 peptide-pulsed dendritic cells (MART-1/DC). Blood T cell phenotypes and functionality were characterized by flow cytometry before and after treatment. iNKT cells exhibited the central memory phenotype and showed polyfunctional cytokine production. In the combination treatment group, high frequencies of pro-inflammatory Th1 iNKT CD8(+) cells correlated with positive clinical responses. These results indicate that iNKT cells play a critical role in regulating effective antitumor T cell activity.
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- 2013
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17. Biologically-directed modeling reflects cytolytic clearance of SIV-infected cells in vivo in macaques.
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W David Wick and Otto O Yang
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Medicine ,Science - Abstract
The disappointing outcomes of cellular immune-based vaccines against HIV-1 despite strong evidence for the protective role of CD8⁺ T lymphocytes (CTLs) has prompted revisiting the mechanisms of cellular immunity. Prior data from experiments examining the kinetics of Simian Immunodeficiency Virus (SIV) clearance in infected macaques with or without in vivo CD8 depletion were interpreted as refuting the concept that CTLs suppress SIV/HIV by direct killing of infected cells. Here we briefly review the biological evidence for CTL cytolytic activity in viral infections, and utilize biologically-directed modeling to assess the possibility of a killing mechanism for the antiviral effect of CTLs, taking into account the generation, proliferation, and survival of activated CD4⁺ and CD8⁺ T lymphocytes, as well as the life cycle of the virus. Our analyses of the published macaque data using these models support a killing mechanism, when one considers T lymphocyte and HIV-1 lifecycles, and factors such as the eclipse period before release of virions by infected cells, an exponential pattern of virion production by infected cells, and a variable lifespan for acutely infected cells. We conclude that for SIV/HIV pathogenesis, CTLs deserve their reputation as being cytolytic.
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- 2012
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18. Protection against bronchiolitis obliterans syndrome is associated with allograft CCR7+ CD45RA- T regulatory cells.
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Aric L Gregson, Aki Hoji, Vyacheslav Palchevskiy, Scott Hu, S Samuel Weigt, Eileen Liao, Ariss Derhovanessian, Rajeev Saggar, Sophie Song, Robert Elashoff, Otto O Yang, and John A Belperio
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Medicine ,Science - Abstract
Bronchiolitis obliterans syndrome (BOS) is the major obstacle to long-term survival after lung transplantation, yet markers for early detection and intervention are currently lacking. Given the role of regulatory T cells (Treg) in modulation of immunity, we hypothesized that frequencies of Treg in bronchoalveolar lavage fluid (BALF) after lung transplantation would predict subsequent development of BOS. Seventy BALF specimens obtained from 47 lung transplant recipients were analyzed for Treg lymphocyte subsets by flow cytometry, in parallel with ELISA measurements of chemokines. Allograft biopsy tissue was stained for chemokines of interest. Treg were essentially all CD45RA(-), and total Treg frequency did not correlate to BOS outcome. The majority of Treg were CCR4(+) and CD103(-) and neither of these subsets correlated to risk for BOS. In contrast, higher percentages of CCR7(+) Treg correlated to reduced risk of BOS. Additionally, the CCR7 ligand CCL21 correlated with CCR7(+) Treg frequency and inversely with BOS. Higher frequencies of CCR7(+) CD3(+)CD4(+)CD25(hi)Foxp3(+)CD45RA(-) lymphocytes in lung allografts is associated with protection against subsequent development of BOS, suggesting that this subset of putative Treg may down-modulate alloimmunity. CCL21 may be pivotal for the recruitment of this distinct subset to the lung allograft and thereby decrease the risk for chronic rejection.
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- 2010
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19. Candidate vaccine sequences to represent intra- and inter-clade HIV-1 variation.
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Otto O Yang
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Medicine ,Science - Abstract
A likely key factor in the failure of a HIV-1 vaccine based on cytotoxic T lymphocytes (CTL) is the natural immunodominance of epitopes that fall in variable regions of the proteome, which both increases the chance of epitope sequence mismatch with the incoming challenge strain and replicates the pathogenesis of early CTL failure due to epitope escape mutation during natural infection. To identify potential vaccine sequences to focus the CTL response on highly conserved epitopes, the whole proteomes of HIV-1 clades A1, B, C, and D were assessed for Shannon entropy at each amino acid position. Highly conserved regions in Gag (cGag-1, Gag 148-214, and cGag-2, Gag 253-331), Env (cEnv, Env 521-606), and Nef (cNef, Nef 106-148) were identified across clades. Inter- and intra-clade variability of amino acids within the regions tended to overlap, suggesting that polyvalent representation of consensus sequences for the four clades would allow broad HIV-1 strain representation. These four conserved regions were rich in both known and predicted CTL epitopes presented by a breadth of HLA types, and screening of 54 persons with chronic HIV-1 infection revealed that these regions are commonly immunogenic in the context of natural infection. These data suggest that vaccine delivery of a 16-valent mixture of these regions could focus the CTL response against conserved epitopes that are broadly representative of circulating HIV-1 strains.
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- 2009
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20. Remdesivir for the Prevention of Invasive Mechanical Ventilation or Death in Coronavirus Disease 2019 (COVID-19): A Post Hoc Analysis of the Adaptive COVID-19 Treatment Trial-1 Cohort Data
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Constance A. Benson, Otto O. Yang, Sarah B Doernberg, Robert Grossberg, Jing Wang, David C. Lye, Philip O Ponce, Cameron R. Wolfe, Richard T. Davey, Shannon K. Gallagher, Lori E. Dodd, Jocelyn Voell, Rekha R. Rapaka, William R. Short, Noreen A. Hynes, and Catharine I. Paules
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Microbiology (medical) ,Mechanical ventilation ,medicine.medical_specialty ,Coronavirus disease 2019 (COVID-19) ,business.industry ,medicine.medical_treatment ,Infectious Diseases ,Risk groups ,Treatment trial ,Oxygen breathing ,Emergency medicine ,Cohort ,Post-hoc analysis ,medicine ,Treatment effect ,business - Abstract
This post hoc analysis of the Adaptive Coronavirus Disease 2019 (COVID-19) Treatment Trial-1 (ACTT-1) shows a treatment effect of remdesivir (RDV) on progression to invasive mechanical ventilation (IMV) or death. Additionally, we create a risk profile that better predicts progression than baseline oxygen requirement alone. The highest risk group derives the greatest treatment effect from RDV.
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- 2021
21. Clinical Characteristics and Outcomes of Coronavirus Disease 2019 Patients Who Received Compassionate-Use Leronlimab
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Kush Dhody, Otto O. Yang, Bryant Yang, Jonathan Fulcher, Arash Naeim, David Goodman-Meza, Jenny Ahn, Marlene Berro, and Jonah B. Sacha
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0301 basic medicine ,Microbiology (medical) ,medicine.medical_specialty ,medicine.medical_treatment ,Lymphocyte ,Clinical Trials and Supportive Activities ,HIV Antibodies ,Passive ,Loading dose ,Microbiology ,Medical and Health Sciences ,Antibodies ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Tocilizumab ,Clinical Research ,Internal medicine ,Monoclonal ,medicine ,80 and over ,Humans ,030212 general & internal medicine ,Dosing ,Humanized ,Aged ,Mechanical ventilation ,biology ,business.industry ,SARS-CoV-2 ,Inflammatory and immune system ,COVID-19 ,Hydroxychloroquine ,leronlimab ,Middle Aged ,Biological Sciences ,Ferritin ,Sarilumab ,030104 developmental biology ,medicine.anatomical_structure ,Infectious Diseases ,Treatment Outcome ,chemistry ,6.1 Pharmaceuticals ,biology.protein ,immunomodulatory therapy ,Immunization ,business ,medicine.drug - Abstract
Background Leronlimab, a monoclonal antibody blocker of C-C chemokine receptor type 5 originally developed to treat human immunodeficiency virus infection, was administered as an open-label compassionate-use therapeutic for coronavirus disease 2019 (COVID-19). Methods Twenty-three hospitalized severe/critical COVID-19 patients received 700 mg leronlimab subcutaneously, repeated after 7 days in 17 of 23 patients still hospitalized. Eighteen of 23 received other experimental treatments, including convalescent plasma, hydroxychloroquine, steroids, and/or tocilizumab. Five of 23 received leronlimab after blinded, placebo-controlled trials of remdesivir, sarilumab, selinexor, or tocilizumab. Outcomes and results were extracted from medical records. Results Mean age was 69.5 ± 14.9 years; 20 had significant comorbidities. At baseline, 22 were receiving supplemental oxygen (3 high flow, 7 mechanical ventilation). Blood showed markedly elevated inflammatory markers (ferritin, D-dimer, C-reactive protein) and an elevated neutrophil-to-lymphocyte ratio. By day 30 after initial dosing, 17 were recovered, 2 were still hospitalized, and 4 had died. Of the 7 intubated at baseline, 4 were fully recovered off oxygen, 2 were still hospitalized, and 1 had died. Conclusions Leronlimab appeared safe and well tolerated. The high recovery rate suggested benefit, and those with lower inflammatory markers had better outcomes. Some, but not all, patients appeared to have dramatic clinical responses, indicating that unknown factors may determine responsiveness to leronlimab. Routine inflammatory and cell prognostic markers did not markedly change immediately after treatment, although interleukin-6 tended to fall. In some persons, C-reactive protein clearly dropped only after the second leronlimab dose, suggesting that a higher loading dose might be more effective. Future controlled trials will be informative.
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- 2021
22. The systemic inflammatory landscape of COVID-19 in pregnancy: Extensive serum proteomic profiling of mother-infant dyads with in utero SARS-CoV-2
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Serpil C. Erzurum, Maria Elisabeth Lopes Moreira, Woo-Jin Shin, Tian Xia, Ruth Cortado, Otto O. Yang, Jenny Y. Mei, Zilton Vasconcelos, Priya R. Soni, Trevon Fuller, Suzy A.A. Comhair, Sherin U. Devaskar, Deisy Contreras, Brenda Asilnejad, Suan-Sin Foo, Kyle L. Jung, Rashmi Rao, Tara Kerin, Debika Bhattacharya, Yvonne J. Bryson, Mary Catherine Cambou, Shangxin Yang, L. Caroline Gibson, Francisco Javier Ibarrondo, Shubhamoy Ghosh, Patrícia Brasil, Jessica Cranston, Thalia Mok, Vaithilingaraja Arumugaswami, Weiqiang Chen, Viviana M. Fajardo, Nicole H. Tobin, Carla Janzen, Grace M. Aldrovandi, Omai B. Garner, Younho Choi, Xin Wu, Jae U. Jung, and Karin Nielsen-Saines
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Serum ,Proteomics ,Medicine (General) ,COVID19 ,serum proteomics ,Reproductive health and childbirth ,Pregnancy ,Infant Mortality ,2.1 Biological and endogenous factors ,Aetiology ,Lung ,Pediatric ,Infectious Diseases ,In utero ,Cord blood ,Cytokines ,Female ,pregnancy ,medicine.symptom ,COVID19-exposed infants ,IFNλ signaling ,prenatal SARS-CoV-2 infection ,Adult ,Pediatric Research Initiative ,Adolescent ,COVID-19-exposed infants ,Mothers ,Inflammation ,Article ,General Biochemistry, Genetics and Molecular Biology ,Proinflammatory cytokine ,Vaccine Related ,Young Adult ,R5-920 ,Immune system ,Clinical Research ,Biodefense ,ESM1 ,medicine ,Humans ,Conditions Affecting the Embryonic and Fetal Periods ,mother-infant pairs ,Proteomic Profiling ,business.industry ,Prevention ,Inflammatory and immune system ,Infant, Newborn ,Infant ,COVID-19 ,IFN-λ signaling ,Perinatal Period - Conditions Originating in Perinatal Period ,medicine.disease ,Newborn ,Emerging Infectious Diseases ,Good Health and Well Being ,Immunology ,business - Abstract
While pregnancy increases the risk for severe COVID19, the clinical and immunological implications of COVID19 on maternal-fetal health remain unknown. Here, we present the clinical and immunological landscapes of 93 COVID19 mothers and 45 of their SARS-CoV-2-exposed infants through comprehensive serum proteomics profiling for >1400 cytokines of their peripheral and cord blood specimens. Prenatal SARS-CoV-2 infection triggers NF-κB-dependent proinflammatory immune activation. Pregnant women with severe COVID19 show increased inflammation and unique IFNλ antiviral signaling, with elevated levels of IFNL1 and IFNLR1. Furthermore, SARS-CoV-2 infection re-shapes maternal immunity at delivery altering the expression of pregnancy complication-associated cytokines, inducing MMP7, MDK, ESM1, and reducing BGN and CD209. Finally, COVID19-exposed infants exhibit induction of T cell-associated cytokines (IL33, NFATC3 and CCL21), while some undergo IL-1β/IL-18/CASP1 axis-driven neonatal respiratory distress despite birth at term. Our findings demonstrate COVID19-induced immune rewiring in both mothers and neonates, warranting long-term clinical follow-up to mitigate potential health risks., Graphical Abstract, The study performed by Foo et al. unveils distinct immune alterations of mothers and infants induced by SARS-CoV-2 infection during pregnancy. These findings highlight the importance of long-term post-pregnancy clinical follow-up of mother-infant dyads to prevent potential unforeseen health conditions following prenatal SARS-CoV-2 infection.
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- 2021
23. Efficacy of interferon beta-1a plus remdesivir compared with remdesivir alone in hospitalised adults with COVID-19: a double-bind, randomised, placebo-controlled, phase 3 trial
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Andre C Kalil, Aneesh K Mehta, Thomas F Patterson, Nathaniel Erdmann, Carlos A Gomez, Mamta K Jain, Cameron R Wolfe, Guillermo M Ruiz-Palacios, Susan Kline, Justino Regalado Pineda, Anne F Luetkemeyer, Michelle S Harkins, Patrick E H Jackson, Nicole M Iovine, Victor F Tapson, Myoung-don Oh, Jennifer A Whitaker, Richard A Mularski, Catharine I Paules, Dilek Ince, Jin Takasaki, Daniel A Sweeney, Uriel Sandkovsky, David L Wyles, Elizabeth Hohmann, Kevin A Grimes, Robert Grossberg, Maryrose Laguio-Vila, Allison A Lambert, Diego Lopez de Castilla, EuSuk Kim, LuAnn Larson, Claire R Wan, Jessica J Traenkner, Philip O Ponce, Jan E Patterson, Paul A Goepfert, Theresa A Sofarelli, Satish Mocherla, Emily R Ko, Alfredo Ponce de Leon, Sarah B Doernberg, Robert L Atmar, Ryan C Maves, Fernando Dangond, Jennifer Ferreira, Michelle Green, Mat Makowski, Tyler Bonnett, Tatiana Beresnev, Varduhi Ghazaryan, Walla Dempsey, Seema U Nayak, Lori Dodd, Kay M Tomashek, John H Beigel, Angela Hewlett, Barbara S Taylor, Jason E Bowling, Ruth C Serrano, Nadine G Rouphael, Zanthia Wiley, Varun K Phadke, Laura Certain, Hannah N Imlay, John J Engemann, Emmanuel B Walter, Jessica Meisner, Sandra Rajme, Joanne Billings, Hyun Kim, Jose A Martinez-Orozco, Nora Bautista Felix, Sammy T Elmor, Laurel R Bristow, Gregory Mertz, Nestor Sosa, Taison D Bell, Miranda J West, Marie-Carmelle Elie-Turenne, Jonathan Grein, Fayyaz Sutterwala, Pyoeng Gyun Choe, Chang Kyung Kang, Hana M El Sahly, Kevin S Rhie, Rezhan H Hussein, Patricia L Winokur, Ayako Mikami, Sho Saito, Constance A Benson, Kimberly McConnell, Mezgebe Berhe, Emma Dishner, Maria G Frank, Ellen Sarcone, Pierre-Cedric B Crouch, Hannah Jang, Nikolaus Jilg, Katherine Perez, Charles Janak, Valeria D Cantos, Paulina A Rebolledo, John Gharbin, Barry S Zingman, Paul F Riska, Ann R Falsey, Edward E Walsh, Angela R Branche, Henry Arguinchona, Christa Arguinchona, Jason W Van Winkle, Diego F Zea, Jongtak Jung, Kyoung-Ho Song, Hong Bin Kim, Jay Dwyer, Emma Bainbridge, David C Hostler, Jordanna M Hostler, Brian T Shahan, Lanny Hsieh, Alpesh N Amin, Miki Watanabe, William R Short, Pablo Tebas, Jillian T Baron, Neera Ahuja, Evelyn Ling, Minjoung Go, Otto O Yang, Jenny Ahn, Rubi Arias, Rekha R Rapaka, Fleesie A Hubbard, James D Campbell, Stuart H Cohen, George R Thompson, Melony Chakrabarty, Stephanie N Taylor, Najy Masri, Alisha Lacour, Tida Lee, Tahaniyat Lalani, David A Lindholm, Ana Elizabeth Markelz, Katrin Mende, Christopher J Colombo, Christina Schofield, Rhonda E Colombo, Faheem Guirgis, Mark Holodniy, Aarthi Chary, Mary Bessesen, Noreen A Hynes, Lauren M Sauer, Vincent C Marconi, Abeer Moanna, Telisha Harrison, David C Lye, Sean W X Ong, Po Ying Chia, Nikhil Huprikar, Anuradha Ganesan, Christian Madar, Richard M Novak, Andrea Wendrow, Scott A Borgetti, Sarah L George, Daniel F Hoft, James D Brien, Susan L F McLellan, Corri Levine, Joy Nock, Seow Yen Tan, Humaira Shafi, Jaime M F Chien, Keith Candiotti, Robert W Finberg, Jennifer P Wang, Mireya Wessolossky, Gregory C Utz, Susan E Chambers, David S Stephens, Timothy H Burgess, Julia Rozman, Yann Hyvert, Andrea Seitzinger, Anu Osinusi, Huyen Cao, Kevin K Chung, Tom M Conrad, Kaitlyn Cross, Jill A El-Khorazaty, Heather Hill, Stephanie Pettibone, Michael R Wierzbicki, Nikki Gettinger, Theresa Engel, Teri Lewis, Jing Wang, Gregory A Deye, Effie Nomicos, Rhonda Pikaart-Tautges, Mohamed Elsafy, Robert Jurao, Hyung Koo, Michael Proschan, Richard Davey, Tammy Yokum, Janice Arega, and Ruth Florese
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Male ,Japan ,Lung ,Singapore ,education.field_of_study ,Alanine ,Maintenance dose ,ACTT-3 study group members ,Hazard ratio ,Rehabilitation ,Middle Aged ,Treatment Outcome ,Infectious Diseases ,6.1 Pharmaceuticals ,Public Health and Health Services ,Female ,Infection ,Interferon beta-1a ,medicine.drug ,Adult ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Population ,Clinical Trials and Supportive Activities ,Clinical Sciences ,Placebo ,Antiviral Agents ,Loading dose ,Double-Blind Method ,Clinical Research ,Internal medicine ,Republic of Korea ,medicine ,Humans ,education ,Adverse effect ,Mexico ,Aged ,Other Medical and Health Sciences ,SARS-CoV-2 ,business.industry ,Comment ,Evaluation of treatments and therapeutic interventions ,Adenosine Monophosphate ,United States ,COVID-19 Drug Treatment ,Oxygen ,Oxygen Saturation ,business ,Breast feeding - Abstract
Summary Background Functional impairment of interferon, a natural antiviral component of the immune system, is associated with the pathogenesis and severity of COVID-19. We aimed to compare the efficacy of interferon beta-1a in combination with remdesivir compared with remdesivir alone in hospitalised patients with COVID-19. Methods We did a double-blind, randomised, placebo-controlled trial at 63 hospitals across five countries (Japan, Mexico, Singapore, South Korea, and the USA). Eligible patients were hospitalised adults (aged ≥18 years) with SARS-CoV-2 infection, as confirmed by a positive RT-PCR test, and who met one of the following criteria suggestive of lower respiratory tract infection: the presence of radiographic infiltrates on imaging, a peripheral oxygen saturation on room air of 94% or less, or requiring supplemental oxygen. Patients were excluded if they had either an alanine aminotransferase or an aspartate aminotransferase concentration more than five times the upper limit of normal; had impaired renal function; were allergic to the study product; were pregnant or breast feeding; were already on mechanical ventilation; or were anticipating discharge from the hospital or transfer to another hospital within 72 h of enrolment. Patients were randomly assigned (1:1) to receive intravenous remdesivir as a 200 mg loading dose on day 1 followed by a 100 mg maintenance dose administered daily for up to 9 days and up to four doses of either 44 μg interferon beta-1a (interferon beta-1a group plus remdesivir group) or placebo (placebo plus remdesivir group) administered subcutaneously every other day. Randomisation was stratified by study site and disease severity at enrolment. Patients, investigators, and site staff were masked to interferon beta-1a and placebo treatment; remdesivir treatment was given to all patients without masking. The primary outcome was time to recovery, defined as the first day that a patient attained a category 1, 2, or 3 score on the eight-category ordinal scale within 28 days, assessed in the modified intention-to-treat population, defined as all randomised patients who were classified according to actual clinical severity. Safety was assessed in the as-treated population, defined as all patients who received at least one dose of the assigned treatment. This trial is registered with ClinicalTrials.gov , NCT04492475 . Findings Between Aug 5, 2020, and Nov 11, 2020, 969 patients were enrolled and randomly assigned to the interferon beta-1a plus remdesivir group (n=487) or to the placebo plus remdesivir group (n=482). The mean duration of symptoms before enrolment was 8·7 days (SD 4·4) in the interferon beta-1a plus remdesivir group and 8·5 days (SD 4·3) days in the placebo plus remdesivir group. Patients in both groups had a time to recovery of 5 days (95% CI not estimable) (rate ratio of interferon beta-1a plus remdesivir group vs placebo plus remdesivir 0·99 [95% CI 0·87–1·13]; p=0·88). The Kaplan-Meier estimate of mortality at 28 days was 5% (95% CI 3–7%) in the interferon beta-1a plus remdesivir group and 3% (2–6%) in the placebo plus remdesivir group (hazard ratio 1·33 [95% CI 0·69–2·55]; p=0·39). Patients who did not require high-flow oxygen at baseline were more likely to have at least one related adverse event in the interferon beta-1a plus remdesivir group (33 [7%] of 442 patients) than in the placebo plus remdesivir group (15 [3%] of 435). In patients who required high-flow oxygen at baseline, 24 (69%) of 35 had an adverse event and 21 (60%) had a serious adverse event in the interferon beta-1a plus remdesivir group compared with 13 (39%) of 33 who had an adverse event and eight (24%) who had a serious adverse event in the placebo plus remdesivir group. Interpretation Interferon beta-1a plus remdesivir was not superior to remdesivir alone in hospitalised patients with COVID-19 pneumonia. Patients who required high-flow oxygen at baseline had worse outcomes after treatment with interferon beta-1a compared with those given placebo. Funding The National Institute of Allergy and Infectious Diseases (USA).
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- 2021
24. Correction for Balamurugan et al., 'Cross-Reactivity against Multiple HIV-1 Epitopes Is Characteristic of HIV-1-Specific Cytotoxic T Lymphocyte Clones'
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Hwee L. Ng, Otto O. Yang, and Arumugam Balamurugan
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Agricultural and Veterinary Sciences ,Immunology ,Human immunodeficiency virus (HIV) ,Biology ,Biological Sciences ,medicine.disease_cause ,Microbiology ,Cross-reactivity ,Virology ,Medical and Health Sciences ,Epitope ,Insect Science ,medicine ,Cytotoxic T cell - Published
- 2021
25. Serological Responses to Toxoplasma gondii and Matrix Antigen 1 Predict the Risk of Subsequent Toxoplasmic Encephalitis in People Living With Human Immunodeficiency Virus (HIV)
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Eric C. Seaberg, Fiona Bhondoekhan, Robert H. Yolken, Otto O. Yang, Valentina Stosor, Jianchun Xiao, Raphael P. Viscidi, and Joseph B. Margolick
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Multicenter AIDS Cohort Study ,Antibodies, Protozoan ,HIV Infections ,Medical and Health Sciences ,Serology ,Cohort Studies ,0302 clinical medicine ,Medicine ,030212 general & internal medicine ,matrix antigen 1 ,predict ,biology ,Biological Sciences ,serological responses ,Infectious Diseases ,Toxoplasmosis, Cerebral ,Protozoan ,Encephalitis ,HIV/AIDS ,Antibody ,Infection ,Toxoplasma ,Toxoplasmosis ,Microbiology (medical) ,Cerebral ,030231 tropical medicine ,Toxoplasma gondii ,Enzyme-Linked Immunosorbent Assay ,Microbiology ,Antibodies ,Vaccine Related ,03 medical and health sciences ,toxoplasmic encephalitis ,Antigen ,Clinical Research ,Humans ,Online Only Articles ,business.industry ,Prevention ,Inflammatory and immune system ,HIV ,Odds ratio ,biology.organism_classification ,medicine.disease ,Emerging Infectious Diseases ,Immunoglobulin G ,Case-Control Studies ,Immunology ,Nested case-control study ,biology.protein ,business - Abstract
Background Clinically useful predictors for fatal toxoplasmosis are lacking. We investigated the value of serological assays for antibodies to whole Toxoplasma antigens and to peptide antigens of the Toxoplasma cyst matrix antigen 1 (MAG1), for predicting incident toxoplasmic encephalitis (TE) in people living with human immunodeficiency virus (HIV; PLWH). Methods We performed a nested case control study, conducted within the Multicenter AIDS Cohort Study (MACS), using serum samples obtained 2 years prior to diagnosis of TE from 28 cases, and 37 HIV disease-matched Toxoplasma seropositive controls at matched time-points. Sera were tested for Toxoplasma antibodies using a commercial assay and for antibodies to MAG1_4.2 and MAG1_5.2 peptides in enzyme-linked immunosorbent assay (ELISA). Results Two years prior to clinical diagnosis, 68% of TE cases were MAG1_4.2 seropositive compared with 16% of controls (odds ratio [OR] 25.0, 95% confidence interval [CI] 3.14–199.18). Corresponding results for MAG1_5.2 seropositivity were 36% and 14% (OR 3.6, 95% CI .95–13.42). Higher levels of antibody to MAG1_4.2 (OR 18.5 per doubling of the optical density [OD] value, 95% CI 1.41–242) and to Toxoplasma (OR 2.91 for each OD unit increase, 95% CI 1.48–5.72) were also associated with the risk of TE. When seropositivity was defined as the presence of MAG1 antibody or relatively high levels of Toxoplasma antibody, the sensitivity was 89% and specificity was 68% for subsequent TE. Conclusions Antibodies to MAG1 showed predictive value on the occurrence of TE in PLWH, and the predictive performance was further improved by adding the levels of Toxoplasma antibody. These measures could be clinically useful for predicting subsequent diseases in multiple at-risk populations.
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- 2021
26. HLA-E–restricted HIV-1–specific CD8+ T cell responses in natural infection
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Leon A. Venegas, Anju Bansal, Ayub Ali, Paul A. Goepfert, Otto O. Yang, Margaret C Costanzo, Jianming Tang, Mark A. Brockman, Kai Qin, Ying Dang, N. Manjunath, Mika N Gehre, Sarah Sterrett, Sojan Abraham, and June Kan-Mitchell
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Receptors, Antigen, T-Cell, alpha-beta ,T cell ,HIV Infections ,Human leukocyte antigen ,Immunodominance ,CD8-Positive T-Lymphocytes ,In Vitro Techniques ,Biology ,Major histocompatibility complex ,gag Gene Products, Human Immunodeficiency Virus ,Epitope ,Cell Line ,Immune system ,HIV Seronegativity ,medicine ,Humans ,Cytotoxic T cell ,Amino Acid Sequence ,Antigen Presentation ,Immunodominant Epitopes ,Histocompatibility Antigens Class I ,General Medicine ,medicine.anatomical_structure ,HLA-B Antigens ,Immunology ,HIV-1 ,biology.protein ,CD8 ,Research Article - Abstract
CD8(+) T cell responses restricted by MHC-E, a nonclassical MHC molecule, have been associated with protection in an SIV/rhesus macaque model. The biological relevance of HLA-E–restricted CD8(+) T cell responses in HIV infection, however, remains unknown. In this study, CD8(+) T cells responding to HIV-1 Gag peptides presented by HLA-E were analyzed. Using in vitro assays, we observed HLA-E–restricted T cell responses to what we believe to be a newly identified subdominant Gag-KL9 as well as a well-described immunodominant Gag-KF11 epitope in T cell lines derived from chronically HIV-infected patients and also primed from healthy donors. Blocking of the HLA-E/KF11 binding by the B7 signal peptide resulted in decreased CD8(+) T cell responses. KF11 presented via HLA-E in HIV-infected cells was recognized by antigen-specific CD8(+) T cells. Importantly, bulk CD8(+) T cells obtained from HIV-infected individuals recognized infected cells via HLA-E presentation. Ex vivo analyses at the epitope level showed a higher responder frequency of HLA-E–restricted responses to KF11 compared with KL9. Taken together, our findings of HLA-E–restricted HIV-specific immune responses offer intriguing and possibly paradigm-shifting insights into factors that contribute to the immunodominance of CD8(+) T cell responses in HIV infection.
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- 2021
27. Performance Analysis of the National Early Warning Score and Modified Early Warning Score in the Adaptive COVID-19 Treatment Trial Cohort
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Christopher J. Colombo, MD, MA, FACP, FCCM, Rhonda E. Colombo, MD, MHS, FACP, FIDSA, Ryan C. Maves, MD, FCCM, FCCP, FIDSA, Angela R. Branche, MD, Stuart H. Cohen, MD, Marie-Carmelle Elie, MD, Sarah L. George, MD, Hannah J. Jang, PhD, RN, CNL, PHN, Andre C. Kalil, MD, MPH, David A. Lindholm, MD, FACP, Richard A. Mularski, MD, MSHS, MCR, ATSF, FCCP, FACP, Justin R. Ortiz, MD, MS, FACP, FCCP, Victor Tapson, MD, C. Jason Liang, PhD, On behalf of the ACTT-1 Study Group, Aneesh K. Mehta, Nadine G. Rouphael, Jessica J. Traenkner, Valeria D Cantos, Ghina Alaaeddine, Barry S. Zingman, Robert Grossberg, Paul F. Riska, Elizabeth Hohmann, Mariam Torres-Soto, Nikolaus Jilg, Helen Y. Chu, Anna Wald, Margaret Green, Annie Luetkemeyer, Pierre-Cedric B. Crouch, Hannah Jang, Susan Kline, Joanne Billings, Brooke Noren, Diego Lopez de Castilla, Jason W. Van Winkle, Francis X. Riedo, Robert W. Finberg, Jennifer P. Wang, Mireya Wessolossky, Kerry Dierberg, Benjamin Eckhardt, Henry J Neumann, Victor Tapson, Jonathan Grein, Fayyaz Sutterwala, Lanny Hsieh, Alpesh N. Amin, Thomas F. Patterson, Heta Javeri, Trung Vu, Roger Paredes, Lourdes Mateu, Daniel A. Sweeney, Constance A. Benson, Farhana Ali, William R. Short, Pablo Tebas, Jessie Torgersen, Giota Touloumi, Vicky Gioukari, David Chien Lye, Sean WX Ong, Norio Ohmagari, Ayako Mikami, Gerd Fätkenheuer, Jakob J. Malin, Philipp Koehler, Andre C. Kalil, LuAnn Larson, Angela Hewlett, Mark G. Kortepeter, C. Buddy Creech, Isaac Thomsen, Todd W. Rice, Babafemi Taiwo, Karen Krueger, Stuart H. Cohen, George R. Thompson, 3rd, Cameron Wolfe, Emmanuel B. Walter, Maria Frank, Heather Young, Ann R. Falsey, Angela R. Branche, Paul Goepfert, Nathaniel Erdmann, Otto O. Yang, Jenny Ahn, Anna Goodman, Blair Merrick, Richard M. Novak, Andrea Wendrow, Henry Arguinchona, Christa Arguinchona, Sarah L. George, Janice Tennant, Robert L. Atmar, Hana M. El Sahly, Jennifer Whitaker, D. Ashley Price, Christopher J. A. Duncan, Simeon Metallidis, Theofilos Chrysanthidis, F. McLellan, Myoung-don Oh, Wan Beom Park, Eu Suk Kim, Jongtak Jung, Justin R. Ortiz, Karen L. Kotloff, Brian Angus, Jack David Germain Seymour, Noreen A. Hynes, Lauren M. Sauer, Neera Ahuja, Kari Nadeau, Patrick E. H. Jackson, Taison D. Bell, Anastasia Antoniadou, Konstantinos Protopapas, Richard T Davey, Jocelyn D. Voell, Jose Muñoz, Montserrat Roldan, Ioannis Kalomenidis, Spyros G. Zakynthinos, Catharine I. Paules, Fiona McGill, Jane Minton, Nikolaos Koulouris, Zafeiria Barmparessou, Edwin Swiatlo, Kyle Widmer, Nikhil Huprikar, Anuradha Ganesan, Guillermo M. Ruiz-Palacios, Alfredo Ponce de León, Sandra Rajme, Justino Regalado Pineda, José Arturo Martinez-Orozco, Mark Holodniy, Aarthi Chary, Timo Wolf, Christoph Stephan, Jan-Christian Wasmuth, Christoph Boesecke, Martin Llewelyn, Barbara Philips, Christopher J. Colombo, Rhonda E. Colombo, David A. Lindholm, Katrin Mende, Tida Lee, Tahaniyat Lalani, Ryan C. Maves, Gregory C. Utz, Jens Lundgren, Marie Helleberg, Jan Gerstoft, Thomas Benfield, Tomas Jensen, Birgitte Lindegaard, Lothar Weise, Lene Knudsen, Isik Johansen, Lone W Madsen, Lars Østergaard, Nina Stærke, Henrik Nielsen, Timothy H. Burgess, Michelle Green, Mat Makowski, Jennifer L. Ferreira, Michael R. Wierzbicki, Tyler Bonnett, Nikki Gettinger, Theresa Engel, Jing Wang, John H. Beigel, Kay M. Tomashek, Seema Nayak, Lori E. Dodd, Walla Dempsey, Effie Nomicos, Marina Lee, Peter Wolff, Rhonda PikaartTautges, Mohamed Elsafy, Robert Jurao, Hyung Koo, Michael Proschan, Dean Follmann, and H. Clifford Lane
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Mechanical ventilation ,medicine.medical_specialty ,Receiver operating characteristic ,Coronavirus disease 2019 (COVID-19) ,business.industry ,RC86-88.9 ,medicine.medical_treatment ,Psychological intervention ,Medical emergencies. Critical care. Intensive care. First aid ,General Medicine ,Early warning score ,Placebo ,Triage ,Internal medicine ,Cohort ,medicine ,Original Clinical Report ,business - Abstract
OBJECTIVES:. We sought to validate prognostic scores in coronavirus disease 2019 including National Early Warning Score, Modified Early Warning Score, and age-based modifications, and define their performance characteristics. DESIGN:. We analyzed prospectively collected data from the Adaptive COVID-19 Treatment Trial. National Early Warning Score was collected daily during the trial, Modified Early Warning Score was calculated, and age applied to both scores. We assessed prognostic value for the end points of recovery, mechanical ventilation, and death for score at enrollment, average, and slope of score over the first 48 hours. SETTING:. A multisite international inpatient trial. PATIENTS:. A total of 1,062 adult nonpregnant inpatients with severe coronavirus disease 2019 pneumonia. INTERVENTIONS:. Adaptive COVID-19 Treatment Trial 1 randomized participants to receive remdesivir or placebo. The prognostic value of predictive scores was evaluated in both groups separately to assess for differential performance in the setting of remdesivir treatment. MEASUREMENTS AND MAIN RESULTS:. For mortality, baseline National Early Warning Score and Modified Early Warning Score were weakly to moderately prognostic (c-index, 0.60–0.68), and improved with addition of age (c-index, 0.66–0.74). For recovery, baseline National Early Warning Score and Modified Early Warning Score demonstrated somewhat better prognostic ability (c-index, 0.65–0.69); however, National Early Warning Score+age and Modified Early Warning Score+age further improved performance (c-index, 0.68–0.71). For deterioration, baseline National Early Warning Score and Modified Early Warning Score were weakly to moderately prognostic (c-index, 0.59–0.69) and improved with addition of age (c-index, 0.63–0.70). All prognostic performance improvements due to addition of age were significant (p < 0.05). CONCLUSIONS:. In the Adaptive COVID-19 Treatment Trial 1 cohort, National Early Warning Score and Modified Early Warning Score demonstrated moderate prognostic performance in patients with severe coronavirus disease 2019, with improvement in predictive ability for National Early Warning Score+age and Modified Early Warning Score+age. Area under receiver operating curve for National Early Warning Score and Modified Early Warning Score improved in patients receiving remdesivir versus placebo early in the pandemic for recovery and mortality. Although these scores are simple and readily obtainable in myriad settings, in our data set, they were insufficiently predictive to completely replace clinical judgment in coronavirus disease 2019 and may serve best as an adjunct to triage, disposition, and resourcing decisions.
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- 2021
28. Primary, Recall, and Decay Kinetics of SARS-CoV-2 Vaccine Antibody Responses
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Mary Ann Hausner, Otto O. Yang, William Mu, Jonathan Fulcher, Ellie Taus, Scott G. Kitchen, David Goodman-Meza, F. Javier Ibarrondo, Paul Krogstad, Julie Elliott, Ayub Ali, Arumugam Balamurugan, Grace M. Aldrovandi, Kathie G Ferbas, Nicole H. Tobin, Anne W. Rimoin, and Christian Hofmann
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and promotion of well-being ,General Physics and Astronomy ,02 engineering and technology ,Antibodies, Viral ,01 natural sciences ,Neutralization ,humoral immunity ,Medicine ,General Materials Science ,Viral ,Neutralizing ,anti-RBD antibodies ,Lung ,biology ,Vaccination ,General Engineering ,021001 nanoscience & nanotechnology ,Infectious Diseases ,3.4 Vaccines ,Pneumonia & Influenza ,Antibody ,0210 nano-technology ,Infection ,Biotechnology ,vaccine response durability ,COVID-19 Vaccines ,Coronavirus disease 2019 (COVID-19) ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,010402 general chemistry ,Antibodies ,Vaccine Related ,Biodefense ,Humans ,Potency ,Nanoscience & Nanotechnology ,business.industry ,SARS-CoV-2 ,Prevention ,COVID-19 ,Viral Vaccines ,Pneumonia ,Prevention of disease and conditions ,Antibodies, Neutralizing ,0104 chemical sciences ,mRNA nanoparticle vaccine ,Good Health and Well Being ,Antibody response ,Emerging Infectious Diseases ,Antibody Formation ,Immunology ,Humoral immunity ,biology.protein ,Immunization ,business - Abstract
Studies of two SARS-CoV-2 mRNA vaccines suggested that they yield ∼95% protection from symptomatic infection at least short-term, but important clinical questions remain. It is unclear how vaccine-induced antibody levels quantitatively compare to the wide spectrum induced by natural SARS-CoV-2 infection. Vaccine response kinetics and magnitudes in persons with prior COVID-19 compared to virus-naı̈ve persons are not well-defined. The relative stability of vaccine-induced versus infection-induced antibody levels is unclear. We addressed these issues with longitudinal assessments of vaccinees with and without prior SARS-CoV-2 infection using quantitative enzyme-linked immunosorbent assay (ELISA) of anti-RBD antibodies. SARS-CoV-2-naı̈ve individuals achieved levels similar to mild natural infection after the first vaccination; a second dose generated levels approaching severe natural infection. In persons with prior COVID-19, one dose boosted levels to the high end of severe natural infection even in those who never had robust responses from infection, increasing no further after the second dose. Antiviral neutralizing assessments using a spike-pseudovirus assay revealed that virus-naı̈ve vaccinees did not develop physiologic neutralizing potency until the second dose, while previously infected persons exhibited maximal neutralization after one dose. Finally, antibodies from vaccination waned similarly to natural infection, resulting in an average of ∼90% loss within 90 days. In summary, our findings suggest that two doses are important for quantity and quality of humoral immunity in SARS-CoV-2-naı̈ve persons, while a single dose has maximal effects in those with past infection. Antibodies from vaccination wane with kinetics very similar to that seen after mild natural infection; booster vaccinations will likely be required.
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- 2021
29. Robust CAR-T memory formation and function via hematopoietic stem cell delivery
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Valerie Rezek, Anjie Zhen, Mayra A. Carrillo, Jerome A. Zack, Philip Hamid, Otto O. Yang, Wenli Mu, Scott G. Kitchen, Heather Martin, Irvin S. Y. Chen, and Douek, Daniel C
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RNA viruses ,medicine.medical_treatment ,Cellular differentiation ,HIV Infections ,Pathology and Laboratory Medicine ,Lymphocyte Activation ,Regenerative Medicine ,White Blood Cells ,Mice ,Spectrum Analysis Techniques ,0302 clinical medicine ,Immunodeficiency Viruses ,Animal Cells ,Cellular types ,Receptors ,Medicine and Health Sciences ,Cytotoxic T cell ,Biology (General) ,0303 health sciences ,Receptors, Chimeric Antigen ,T Cells ,Stem Cells ,Immune cells ,Hematopoietic stem cell ,CD28 ,Cell Differentiation ,Gene Therapy ,Flow Cytometry ,Infectious Diseases ,medicine.anatomical_structure ,Spectrophotometry ,Medical Microbiology ,Viral Pathogens ,Antigen ,030220 oncology & carcinogenesis ,Viruses ,Infectious diseases ,HIV/AIDS ,Cytophotometry ,Pathogens ,Development of treatments and therapeutic interventions ,Stem cell ,Infection ,Research Article ,HIV infections ,Biotechnology ,Medical conditions ,Cell biology ,Blood cells ,QH301-705.5 ,T cell ,Immunology ,Receptors, Antigen, T-Cell ,Cytotoxic T cells ,Viral diseases ,Biology ,Research and Analysis Methods ,Microbiology ,Vaccine Related ,03 medical and health sciences ,Virology ,Retroviruses ,Genetics ,medicine ,Animals ,Humans ,Molecular Biology Techniques ,Microbial Pathogens ,Molecular Biology ,030304 developmental biology ,Transplantation ,Biology and life sciences ,5.2 Cellular and gene therapies ,Lentivirus ,Organisms ,Correction ,HIV ,Chimeric Antigen ,Immunotherapy ,RC581-607 ,Hematopoietic Stem Cells ,T-Cell ,Stem Cell Research ,Chimeric antigen receptor ,HIV-1 ,Cancer research ,Immunization ,Parasitology ,Immunologic diseases. Allergy ,Developmental Biology ,Cloning - Abstract
Due to the durability and persistence of reservoirs of HIV-1-infected cells, combination antiretroviral therapy (ART) is insufficient in eradicating infection. Achieving HIV-1 cure or sustained remission without ART treatment will require the enhanced and persistent effective antiviral immune responses. Chimeric Antigen Receptor (CAR) T-cells have emerged as a powerful immunotherapy and show promise in treating HIV-1 infection. Persistence, trafficking, and maintenance of function remain to be a challenge in many of these approaches, which are based on peripheral T cell modification. To overcome many of these issues, we have previously demonstrated successful long-term engraftment and production of anti-HIV CAR T cells in modified hematopoietic stem cells (HSCs) in vivo. Here we report the development and in vivo testing of second generation CD4-based CARs (CD4CAR) against HIV-1 infection using a HSCs-based approach. We found that a modified, truncated CD4-based CAR (D1D2CAR) allows better CAR-T cell differentiation from gene modified HSCs, and maintains similar CTL activity as compared to the full length CD4-based CAR. In addition, D1D2CAR does not mediate HIV infection or stimulation mediated by IL-16, suggesting lower risk of off-target effects. Interestingly, stimulatory domains of 4-1BB but not CD28 allowed successful hematopoietic differentiation and improved anti-viral function of CAR T cells from CAR modified HSCs. Addition of 4-1BB to CD4 based CARs led to faster suppression of viremia during early untreated HIV-1 infection. D1D2CAR 4-1BB mice had faster viral suppression in combination with ART and better persistence of CAR T cells during ART. In summary, our data indicate that the D1D2CAR-41BB is a superior CAR, showing better HSC differentiation, viral suppression and persistence, and less deleterious functions compared to the original CD4CAR, and should continue to be pursued as a candidate for clinical study., Author summary Engineering T cells with anti-HIV chimeric antigen receptors (CAR) has emerged as a promising strategy to control HIV infection through a genetic vaccination strategy. Here we report a novel CAR-based approach targeting HIV infection using the genetic modification of blood forming hematopoietic stem cells (HSCs). This novel CAR approach uses a modified HIV receptor molecule (the primary HIV receptor CD4) as well as anti-HIV agents to modify HSCs to allow them to develop into cells that are protected from HIV infection and target HIV infected cells for the life of the individual. We found this latest generation of CARs successfully modified and allowed in vivo engraftment that resulted in the development of effective anti-HIV CAR T cells with robust memory formation and viral control. Our study highlights the identification of a next-generation CAR molecule that protected cells from infection, targeted and reduced HIV burdens, and serves as an ideal developmental candidate for further clinical studies.
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- 2021
30. Induction of Autophagy Reduces IFN-I Mediated Inflammation and Restores Anti-HIV-1 T Cell Response in vivo
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Mayra A. Carrillo, Beth D. Jamieson, Valerie Rezek, Scott G. Kitchen, Miguel Lizarraga, Heather Martin, Anjie Zhen, Otto O. Yang, Wenli Mu, and Philip Hamid
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Cellular immunity ,business.industry ,T cell ,Intracellular parasite ,Autophagy ,Cellular homeostasis ,Inflammation ,Pathogenesis ,medicine.anatomical_structure ,Interferon ,Cancer research ,Medicine ,medicine.symptom ,business ,medicine.drug - Abstract
A hallmark of HIV-1 infection is chronic inflammation. Chronic immune activation drives the pathogenesis of HIV-1 infection, leading to loss of CD4+ T cells and exhaustion of antiviral cellular immunity. Previously, we demonstrated that persistent inflammation mediated by type I interferon (IFN-I) signaling drives T cell exhaustion. Combination of anti-retroviral therapy (ART) and IFN-I receptor blockade therapy led to accelerated viral suppression and reduced latent HIV-1 reservoirs, suggesting that targeting type I IFN signaling can be used as a therapeutic strategy to alleviate T cell exhaustion. However, as IFN-Is are key regulators for antiviral immunity, more specific interventions to fine-tune IFN-I signaling and chronic inflammation are needed. Autophagy is a homeostatic mechanism for disposal of damaged cellular organelles and elimination of intracellular pathogens, which is pivotal for cellular homeostasis, T cell development and function. Autophagy is also impaired during HIV-1 infection. Here we demonstrate that autophagy is directly linked to IFN-I signaling. Impairment of autophagy leads to accumulation of damaged mitochondria and spontaneous IFN-I signaling. Autophagy inducers reduce IFN-I signaling in activated macrophages and restore functions of exhausted anti-HIV-1 T cells in vitro. Importantly, autophagy inducer treatment in HIV-1 infected humanized bone marrow/liver/thymus (BLT) mice significantly reduced persistent IFN-I signaling and immune activation, restored exhausted antiviral T cell responses, and accelerated viral suppression by ART. Autophagy inducer treatment also led to reduced viral rebound after ART withdrawal. Taken together, our data suggest that therapeutically targeting autophagy could be used to treat persistent immune activation and improve immune control of HIV replication.
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- 2021
31. Humoral responses to SARS-CoV-2 mRNA vaccines: Role of past infection
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Saman Kashani, Megan Halbrook, Rachel Martin-Blais, Christian Hofmann, Otto O. Yang, Clayton Kazan, Yan Wang, Adva Gadoth, Kathie Grovit-Ferbas, Grace M. Aldrovandi, Fan Li, Nicole H. Tobin, Ashley Gray, Anne W. Rimoin, Emmanuelle Faure-Kumar, Julie Elliott, Jonathan Fulcher, Sarah L Brooker, and Nasrallah, Gheyath K
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RNA viruses ,Emergency Medical Services ,Pulmonology ,Physiology ,Coronaviruses ,Messenger ,Antibody Response ,Antibodies, Viral ,Biochemistry ,California ,Medical Conditions ,Immune Physiology ,Medicine and Health Sciences ,Medicine ,Public and Occupational Health ,Viral ,Respiratory system ,Immune Response ,Lung ,Pathology and laboratory medicine ,Virus Testing ,Immunoassay ,Vaccines ,Academic Medical Centers ,Multidisciplinary ,Immune System Proteins ,medicine.diagnostic_test ,biology ,Antibody titer ,Humoral ,Medical microbiology ,Vaccination and Immunization ,Titer ,Infectious Diseases ,Viruses ,Pneumonia & Influenza ,Antibody ,SARS CoV 2 ,Pathogens ,Infection ,Research Article ,2019-nCoV Vaccine mRNA-1273 ,Biotechnology ,COVID-19 Vaccines ,Infectious Disease Control ,SARS coronavirus ,Universities ,General Science & Technology ,Science ,Health Personnel ,Immunology ,Microbiology ,Antibodies ,Vaccine Related ,Respiratory Disorders ,Immune system ,Diagnostic Medicine ,Clinical Research ,Biodefense ,Humans ,RNA, Messenger ,BNT162 Vaccine ,Messenger RNA ,business.industry ,SARS-CoV-2 ,Prevention ,Organisms ,Viral pathogens ,Immunity ,Emergency Responders ,Biology and Life Sciences ,Proteins ,COVID-19 ,Microbial pathogens ,Immunity, Humoral ,Regimen ,Emerging Infectious Diseases ,Good Health and Well Being ,Respiratory Infections ,Antibody Formation ,biology.protein ,RNA ,Immunization ,Preventive Medicine ,business - Abstract
Two mRNA vaccines (BNT162b2 and mRNA-1273) against severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) are globally authorized as a two-dose regimen. Understanding the magnitude and duration of protective immune responses is vital to curbing the pandemic. We enrolled 461 high-risk health services workers at the University of California, Los Angeles (UCLA) and first responders in the Los Angeles County Fire Department (LACoFD) to assess the humoral responses in previously infected (PI) and infection naïve (NPI) individuals to mRNA-based vaccines (BNT162b2/Pfizer- BioNTech or mRNA-1273/Moderna). A chemiluminescent microparticle immunoassay was used to detect antibodies against SARS-CoV-2 Spike in vaccinees prior to (n = 21) and following each vaccine dose (n = 246 following dose 1 and n = 315 following dose 2), and at days 31–60 (n = 110) and 61–90 (n = 190) following completion of the 2-dose series. Both vaccines induced robust antibody responses in all immunocompetent individuals. Previously infected individuals achieved higher median peak titers (p = 0.002) and had a slower rate of decay (p = 0.047) than infection-naïve individuals. mRNA-1273 vaccinated infection-naïve individuals demonstrated modestly higher titers following each dose (p = 0.005 and p = 0.029, respectively) and slower rates of antibody decay (p = 0.003) than those who received BNT162b2. A subset of previously infected individuals (25%) required both doses in order to reach peak antibody titers. The biologic significance of the differences between previously infected individuals and between the mRNA-1273 and BNT162b2 vaccines remains uncertain, but may have important implications for booster strategies.
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- 2021
32. Incidence of SARS-CoV-2 infection among asymptomatic frontline health workers in Los Angeles County, California
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Jonathan Fulcher, Grace M. Aldrovandi, Halbrook M, Gadoth A, Rachel Martin-Blais, Clayton Kazan, Otto O. Yang, Saman Kashani, Brooker Sl, Kane B, Deisy Contreras, Kathie G Ferbas, Scott G. Kitchen, Grey A, Faure-Kumar E, Nicole H. Tobin, and Anne W. Rimoin
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2019-20 coronavirus outbreak ,medicine.medical_specialty ,Surveillance study ,Coronavirus disease 2019 (COVID-19) ,business.industry ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Internal medicine ,Incidence (epidemiology) ,Health care ,Medicine ,medicine.symptom ,business ,Asymptomatic - Abstract
Beginning April 8, 2020, we enrolled 1787 frontline heath workers who were asymptomatic for COVID-19 into a longitudinal surveillance study. During that time 4 healthcare workers and 6 first responders tested positive for SARS-CoV-2 by RT-PCR. Additionally, 43 healthcare workers and 55 first responders had detectable IgG antibodies to SARS-CoV-2.
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- 2020
33. Rapid Decay of Anti–SARS-CoV-2 Antibodies in Persons with Mild Covid-19
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Grace M. Aldrovandi, Kathie G Ferbas, David Goodman-Meza, F. Javier Ibarrondo, Otto O. Yang, Julie Elliott, Jonathan Fulcher, Mary Ann Hausner, Christian Hofmann, and Nicole H. Tobin
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2019-20 coronavirus outbreak ,biology ,Coronavirus disease 2019 (COVID-19) ,business.industry ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Spike Protein ,General Medicine ,030204 cardiovascular system & hematology ,medicine.disease ,biology.organism_classification ,Virology ,03 medical and health sciences ,Pneumonia ,0302 clinical medicine ,Correspondence ,medicine ,biology.protein ,030212 general & internal medicine ,Antibody ,business ,Viral immunology ,Betacoronavirus - Abstract
Covid-19 Antibodies after Mild Infection Among 34 volunteers who had recovered from mild Covid-19 illness, antiviral antibodies to the receptor-binding domain of the viral spike protein declined wi...
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- 2020
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34. Chimeric Antigen Receptors Targeting Human Cytomegalovirus
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Otto O. Yang, Felix Wussow, Flavia Chiuppesi, Jenny Nguyen, Mindy Kha, Minh Tan Nguyen, Don J. Diamond, Angelina Iniguez, Mary Ann Hausner, and Ayub Ali
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0301 basic medicine ,Human cytomegalovirus ,Adoptive cell transfer ,medicine.medical_treatment ,Adoptive ,Cytomegalovirus ,CD8-Positive T-Lymphocytes ,Antibodies, Viral ,Virus Replication ,Immunotherapy, Adoptive ,Medical and Health Sciences ,Transduction, Genetic ,Receptors ,Immunology and Allergy ,Viral ,Neutralizing antibody ,Neutralizing ,Cancer ,Receptors, Chimeric Antigen ,chimeric antigen receptor ,virus diseases ,Gene Therapy ,Biological Sciences ,Infectious Diseases ,5.1 Pharmaceuticals ,Immunotherapy ,Antibody ,Development of treatments and therapeutic interventions ,Infection ,Biotechnology ,030106 microbiology ,cellular immunity ,Biology ,Microbiology ,Antibodies ,Viral vector ,Vaccine Related ,Major Articles and Brief Reports ,03 medical and health sciences ,Transduction ,Genetic ,medicine ,Genetics ,Humans ,Cell Proliferation ,5.2 Cellular and gene therapies ,Chimeric Antigen ,medicine.disease ,Antibodies, Neutralizing ,Virology ,Chimeric antigen receptor ,030104 developmental biology ,HEK293 Cells ,Good Health and Well Being ,human cytomegalovirus ,biology.protein ,Immunization ,CD8 - Abstract
Human cytomegalovirus (CMV) is a ubiquitous pathogen that causes significant morbidity in some vulnerable populations. Individualized adoptive transfer of ex vivo expanded CMV-specific CD8+ T cells has provided proof-of-concept that immunotherapy can be highly effective, but a chimeric antigen receptor (CAR) approach would provide a feasible method for broad application. We created 8 novel CARs using anti-CMV neutralizing antibody sequences, which were transduced via lentiviral vector into primary CD8+ T cells. All CARs were expressed. Activity against CMV-infected target cells was assessed by release of cytokines (interferon-γ and tumor necrosis factor–α), upregulation of surface CD107a, proliferation, cytolysis of infected cells, and suppression of viral replication. While some CARs showed varying functional activity across these assays, 1 CAR based on antibody 21E9 was consistently superior in all measures. These results support development of a CMV-specific CAR for therapeutic use against CMV and potentially other applications harnessing CMV-driven immunotherapies.
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- 2020
35. Longitudinal COVID-19 Surveillance and Characterization in the Workplace with Public Health and Diagnostic Endpoints
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Manjula Gunawardana, Marc M. Baum, Jessica Breslin, Simon Webster, F. Javier Ibarrondo, John M. Cortez, Richard B. Pyles, Otto O. Yang, Amy Adler, Sofia Rivera, Peter A. Anton, Christina M. Ramirez, and Pasetti, Marcela F
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Male ,0301 basic medicine ,Psychological intervention ,serology ,Medical and Health Sciences ,0302 clinical medicine ,Pandemic ,Health care ,80 and over ,antibodies ,Viral ,Longitudinal Studies ,030212 general & internal medicine ,Child ,Workplace ,Lung ,Aged, 80 and over ,Disease surveillance ,Transmission (medicine) ,Biological Sciences ,Middle Aged ,QR1-502 ,Vaccination ,Infectious Diseases ,surveillance ,Pneumonia & Influenza ,RNA, Viral ,Female ,Public Health ,medicine.symptom ,Infection ,Research Article ,Adult ,medicine.medical_specialty ,Adolescent ,Isolation (health care) ,030106 microbiology ,long-term infection ,Microbiology ,Asymptomatic ,Vaccine Related ,Young Adult ,03 medical and health sciences ,Clinical Research ,Biodefense ,Environmental health ,Genetics ,medicine ,Humans ,asymptomatic ,Pandemics ,Molecular Biology ,Aged ,SARS-CoV-2 ,business.industry ,Prevention ,Public health ,COVID-19 ,Pneumonia ,workplace ,Good Health and Well Being ,Emerging Infectious Diseases ,RNA ,Immunization ,business - Abstract
BackgroundThe rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the associated coronavirus disease 2019 (COVID-19) have precipitated a global pandemic heavily challenging our social behavior, economy, and healthcare infrastructure. Public health practices currently represent the primary interventions for managing the spread of the pandemic. We hypothesized that frequent, longitudinal workplace disease surveillance would represent an effective approach to controlling SARS-CoV-2 transmission among employees and their household members, reducing potential economic consequences and loss of productivity of standard isolation methods, while providing new insights into viral-host dynamics.Methodology and FindingsOn March 23, 2020 a clinical study (OCIS-05) was initiated at a small Southern California organization. Results from the first 3 months of the ongoing study are presented here. Study participants (27 employees and 27 household members) consented to provide frequent nasal or oral swab samples that were analyzed by RT-qPCR for SARS-CoV-2 RNA using CDC protocols. Only participants testing negative were allowed to enter the “safe zone” workplace facility. Optional blood samples were collected at baseline and throughout the 3-month study. Serum virus-specific antibody concentrations (IgG, IgM, and IgA) were measured using a selective, sensitive, and quantitative ELISA assay developed in house. A COVID-19 infection model, based on traditional SEIR compartmental models combined with Bayesian non-linear mixed models and modern machine learning, was used to predict the number of employees and household members who would have become infected in the absence of workplace surveillance.Two study participants were found to be infected by SARS-CoV-2 during the study. One subject, a household member, tested positive clinically by RT-qPCR prior to enrollment and experienced typical COVID-19 symptoms that did not require hospitalization. While on study, the participant was SARS-CoV-2 RNA positive for at least 71 days and had elevated virus-specific antibody concentrations (medians: IgM, 9.83 µg mL-1; IgG, 11.5 µg mL-1; IgA, 1.29 µg mL-1) in serum samples collected at three timepoints. A single, unrelated employee became positive for SARS-CoV-2 RNA over the course of the study, but remained asymptomatic with low associated viral RNA copy numbers. The participant did not have detectable serum IgM and IgG concentrations, and IgA concentrations decayed rapidly (half-life: 1.3 d). The employee was not allowed entry to the safe zone workplace until testing negative three consecutive times over 7 d. No other employees or household members contracted COVID-19 over the course of the study. Our model predicted that under the current prevalence in Los Angeles County without surveillance intervention, up to 7 employees (95% CI = 3-10) would have become infected with at most 1 of them requiring hospitalizations and 0 deaths.ConclusionsOur clinical study met its primary objectives by using intense longitudinal testing to provide a safe work environment during the COVID-19 pandemic, and elucidating SARS-CoV-2 dynamics in recovering and asymptomatic participants. The surveillance plan outlined here is scalable and transferrable. The study represents a powerful example on how an innovative public health initiative can be dovetailed with scientific discovery.
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- 2020
36. A Novel HIV-1 Nef Mutation in a Primary Pediatric Isolate Impairs MHC-Class I Downregulation and Cytopathicity
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Arnaud D. Colantonio, Otto O. Yang, Ayub Ali, Robert L. Furler, Deborah J. Anisman-Posner, Yvonne J. Bryson, Livia Pedroza-Martins, and Christel H. Uittenbogaart
- Subjects
Pediatric AIDS ,HIV Infections ,Pathogenesis ,Mice, SCID ,nef Gene Products ,medicine.disease_cause ,Mice ,Cytopathogenic Effect, Viral ,2.1 Biological and endogenous factors ,2.2 Factors relating to the physical environment ,Viral ,Aetiology ,Child ,Cells, Cultured ,Pediatric ,Mutation ,Cultured ,Thymocytes ,biology ,virus diseases ,Thymocyte ,Infectious Diseases ,Child, Preschool ,HIV/AIDS ,Infection ,Human Immunodeficiency Virus ,Cells ,Immunology ,Clinical Sciences ,Down-Regulation ,cytopathicity ,Major histocompatibility complex ,SCID ,Downregulation and upregulation ,In vivo ,Virology ,MHC class I ,medicine ,Animals ,Humans ,nef Gene Products, Human Immunodeficiency Virus ,Preschool ,MHC-I downregulation ,Nef ,Histocompatibility Antigens Class I ,Infant, Newborn ,Infant ,thymocyte ,Newborn ,In vitro ,biology.protein ,HIV-1 ,Cytopathogenic Effect ,Gene Deletion - Abstract
HIV-1-induced cytopathicity of thymocytes is a major cause of reduced peripheral T cells and rapid disease progression observed in HIV-1-infected infants. Understanding the virulence factors responsible for thymocyte depletion has paramount importance in addressing the pathogenesis of disease progression in children. In this study, thymocyte depletion was analyzed following infection with two primary CXCR4-tropic HIV-1 pediatric isolates (PI), PI-2 and PI-2.1, which were serially derived from an in utero-infected infant. Although highly similar to each other, PI-2 showed markedly decreased thymocyte depletion in vitro compared with PI-2.1. Further analysis showed a novel deletion in the Nef protein (NefΔK7S) of PI-2, which was absent in PI-2.1. This deletion inhibited Nef-mediated major histocompatibility complex class I (MHC-I) downregulation in infected thymocytes in vitro and in vivo; in contrast, the mutated Nef continued to downregulate CD4 surface expression in vitro. These results suggest that HIV-1 Nef contributes to thymic damage in infants through selective functions.
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- 2020
37. CD8+Cytotoxic T Lymphocyte Responses and Viral Epitope Escape in Acute HIV-1 Infection
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Hwee L. Ng, Justin De La Cruz, Joseph M Kim, Otto O. Yang, Arumugam Balamurugan, Eric S. Daar, and Karen Lam
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Cytotoxic ,T-Lymphocytes ,Human immunodeficiency virus (HIV) ,Acute infection ,HIV Infections ,nef Gene Products ,medicine.disease_cause ,Epitope ,Epitopes ,Plasma ,Cytotoxic T cell ,Viral ,Longitudinal Studies ,Infectious Diseases ,T lymphocyte immunity ,Acute Disease ,HIV/AIDS ,RNA, Viral ,Molecular Medicine ,Infection ,Human Immunodeficiency Virus ,gag ,pol ,escape from immune responses ,Primary Cell Culture ,Immunology ,Gene Products, gag ,Gene Products, pol ,chemical and pharmacologic phenomena ,Immune control ,Vaccine Related ,Clinical Research ,Virology ,medicine ,Gene Products ,cell-mediated immunity ,Humans ,nef Gene Products, Human Immunodeficiency Virus ,business.industry ,Prevention ,Original Articles ,Cell mediated immunity ,CTL ,Good Health and Well Being ,HIV-1 ,RNA ,Immunization ,business ,Epitope Mapping ,CD8 ,T-Lymphocytes, Cytotoxic - Abstract
Epitope escape from HIV-1-targeted CD8(+) cytotoxic T lymphocyte (CTL) responses occurs rapidly after acute infection and contributes to the eventual failure of effective immune control of HIV-1 infection. Because the early CTL response is key in determining HIV-1 disease outcome, studying the process of epitope escape is crucial for understanding what leads to failure of immune control in acute HIV-1 infection and will provide important implications for HIV-1 vaccine design. HIV-1-specific CD8(+) T lymphocyte responses against viral epitopes were mapped in six acutely infected individuals, and the magnitudes of these responses were measured longitudinally during acute infection. The evolution of autologous circulating viral epitopes was determined in four of these subjects. In-depth testing of CD8(+) T lymphocyte responses against index and all autologous-detected variant epitopes was performed in one subject. Among the four individuals examined, 10 of a total of 35 CD8(+) T cell responses within Gag, Pol, and Nef showed evidence of epitope escape. CTL responses with viral epitope variant evolution were shown in one subject, and this evolution occurred with and without measurable CTL responses against epitope variants. These results demonstrate a dynamic period of viral epitope evolution in early HIV-1 infection due to CD8(+) CTL response pressure.
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- 2018
38. Correction: Robust CAR-T memory formation and function via hematopoietic stem cell delivery
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Heather Martin, Valerie Rezek, Scott G. Kitchen, Philip Hamid, Otto O. Yang, Wenli Mu, Mayra A. Carrillo, Irvin S. Y. Chen, Jerome A. Zack, and Anjie Zhen
- Subjects
QH301-705.5 ,Immunology ,Hematopoietic stem cell ,RC581-607 ,Biology ,Microbiology ,Cell biology ,medicine.anatomical_structure ,Medical Microbiology ,Virology ,Genetics ,medicine ,Memory formation ,Parasitology ,Immunologic diseases. Allergy ,Biology (General) ,Car t cells ,Molecular Biology ,Function (biology) - Abstract
[This corrects the article DOI: 10.1371/journal.ppat.1009404.].
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- 2021
39. Clinical efficacy of gene-modified stem cells in adenosine deaminase–deficient immunodeficiency
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Sally Shupien, Linda M. Muul, Fabio Candotti, Berkley Brown, Pei Yu Fu, Rob Sokolic, Barbara Nowicki, Otto O. Yang, Aaron R. Cooper, Andrew M. Scharenberg, Christopher Silvin, David W. Gjertson, Alejandra Davila, Kit L. Shaw, Dayna Terrazas, Donald B. Kohn, Alan Ikeda, Beatriz Campo Fernandez, Radha G. Rishi, Neena Kapoor, Xiaoyan Wang, Denise Carbonaro, Suparna Mishra, Arumugam Balamurugan, G. Jayashree Jagadeesh, Satiro N. De Oliveira, Yeong Choi, Kenneth Cornetta, Suzanne Skoda-Smith, Michael S. Hershfield, Roshini S. Abraham, Sabine Geiger, David Buchbinder, Barbara C. Engel, Provaboti Barman, Theodore B. Moore, Kathey Mohan, E. Monika Smogorzewska, Elizabeth Garabedian, Allen Yu, Ken Purdy, John Tse, Greg M. Podsakoff, and Stacie M. Anderson
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Male ,0301 basic medicine ,Oncology ,congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,Adolescent ,Adenosine Deaminase ,Genetic enhancement ,medicine.medical_treatment ,Genetic Vectors ,CD34 ,Hematopoietic stem cell transplantation ,Gene Expression Regulation, Enzymologic ,03 medical and health sciences ,Agammaglobulinemia ,Transduction, Genetic ,immune system diseases ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,Progenitor cell ,Autografts ,Child ,business.industry ,Hematopoietic Stem Cell Transplantation ,Infant ,nutritional and metabolic diseases ,Genetic Therapy ,General Medicine ,medicine.disease ,3. Good health ,Adenosine deaminase deficiency ,Transplantation ,Retroviridae ,surgical procedures, operative ,030104 developmental biology ,Child, Preschool ,Female ,Severe Combined Immunodeficiency ,Clinical Medicine ,Stem cell ,business ,Busulfan ,medicine.drug - Abstract
Background Autologous hematopoietic stem cell transplantation (HSCT) of gene-modified cells is an alternative to enzyme replacement therapy (ERT) and allogeneic HSCT that has shown clinical benefit for adenosine deaminase-deficient (ADA-deficient) SCID when combined with reduced intensity conditioning (RIC) and ERT cessation. Clinical safety and therapeutic efficacy were evaluated in a phase II study. Methods Ten subjects with confirmed ADA-deficient SCID and no available matched sibling or family donor were enrolled between 2009 and 2012 and received transplantation with autologous hematopoietic CD34+ cells that were modified with the human ADA cDNA (MND-ADA) γ-retroviral vector after conditioning with busulfan (90 mg/m2) and ERT cessation. Subjects were followed from 33 to 84 months at the time of data analysis. Safety of the procedure was assessed by recording the number of adverse events. Efficacy was assessed by measuring engraftment of gene-modified hematopoietic stem/progenitor cells, ADA gene expression, and immune reconstitution. Results With the exception of the oldest subject (15 years old at enrollment), all subjects remained off ERT with normalized peripheral blood mononuclear cell (PBMC) ADA activity, improved lymphocyte numbers, and normal proliferative responses to mitogens. Three of nine subjects were able to discontinue intravenous immunoglobulin replacement therapy. The MND-ADA vector was persistently detected in PBMCs (vector copy number [VCN] = 0.1-2.6) and granulocytes (VCN = 0.01-0.3) through the most recent visits at the time of this writing. No patient has developed a leukoproliferative disorder or other vector-related clinical complication since transplant. Conclusion These results demonstrate clinical therapeutic efficacy from gene therapy for ADA-deficient SCID, with an excellent clinical safety profile. Trial registration ClinicalTrials.gov NCT00794508. Funding Food and Drug Administration Office of Orphan Product Development award, RO1 FD003005; NHLBI awards, PO1 HL73104 and Z01 HG000122; UCLA Clinical and Translational Science Institute awards, UL1RR033176 and UL1TR000124.
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- 2017
40. Erratum to: Changes in Bone Mineral Density After Initiation of Antiretroviral Treatment With Tenofovir Disoproxil Fumarate/Emtricitabine Plus Atazanavir/Ritonavir, Darunavir/Ritonavir, or Raltegravir
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James H. Stein, Robert L. Murphy, Todd T. Brown, Theodoros Kelesidis, Grace A. McComsey, Otto O. Yang, Heather J. Ribaudo, Carlee Moser, Judith S. Currier, Michael P. Dubé, and Jennifer Rothenberg
- Subjects
Bone mineral ,Darunavir+Ritonavir ,Tenofovir ,business.industry ,musculoskeletal, neural, and ocular physiology ,Raltegravir ,Emtricitabine ,Virology ,Major Articles and Brief Reports ,Infectious Diseases ,medicine ,Antiretroviral treatment ,Immunology and Allergy ,business ,medicine.drug ,Atazanavir/ritonavir - Abstract
Background. Specific antiretroviral therapy (ART) medications and the severity of human immunodeficiency virus (HIV) disease before treatment contribute to bone mineral density (BMD) loss after ART initiation.
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- 2020
41. Risks Associated With Lentiviral Vector Exposures and Prevention Strategies
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David V. Diamond, Karen Byers, Ryan Schlimgen, Lindsey R. Baden, Otto O. Yang, Jatin M. Vyas, David C. Christiani, Gustavo Mostoslavsky, Thomas Winters, T. Warner Hudson, Gary Fujimoto, Dawn P. Wooley, Jeffrey A. Gelfand, John Howard, Maureen Thompson, and Elizabeth Gilman Duane
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Health Personnel ,Genetic Vectors ,MEDLINE ,Integrase inhibitor ,Nursing ,Risk Assessment ,Environmental & Occupational Health ,Occupational safety and health ,03 medical and health sciences ,Biosafety ,0302 clinical medicine ,Occupational Exposure ,medicine ,Humans ,Adverse effect ,Intensive care medicine ,Occupational Health ,biology ,business.industry ,Lentivirus ,Public Health, Environmental and Occupational Health ,Original Articles ,biology.organism_classification ,Clinical trial ,030104 developmental biology ,030220 oncology & carcinogenesis ,Public Health and Health Services ,Risk assessment ,business - Abstract
Lentiviral vectors (LVVs) are powerful genetic tools that are being used with greater frequency in biomedical laboratories and clinical trials. Adverse events reported from initial clinical studies provide a basis for risk assessment of occupational exposures, yet many questions remain about the potential harm that LVVs may cause. We review those risks and provide a framework for principal investigators, Institutional Biosafety Committees, and occupational health professionals to assess and communicate the risks of exposure to staff. We also provide recommendations to federal research and regulatory agencies for tracking LVV exposures to evaluate long-term outcomes. U.S. Food and Drug Administration approved antiviral drugs for HIV have theoretical benefits in LVV exposures, although evidence to support their use is currently limited. If treatment is appropriate, we recommend a 7-day treatment with an integrase inhibitor with or without a reverse transcriptase inhibitor within 72 hours of exposure.
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- 2016
42. Human Vault Nanoparticle Targeted Delivery of Antiretroviral Drugs to Inhibit Human Immunodeficiency Virus Type 1 Infection
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Valerie A. Kickhoefer, Jonathan Fulcher, Leonard H. Rome, Alexander L. Wollenberg, Julie Elliott, Jan Mrazek, Otto O. Yang, Timothy J. Deming, Peter A. Anton, F. Javier Ibarrondo, Kyle Tamshen, and Heather D. Maynard
- Subjects
Cell type ,Cytoplasm ,Cells ,Mononuclear ,Biomedical Engineering ,Pharmaceutical Science ,Bioengineering ,HIV Infections ,02 engineering and technology ,01 natural sciences ,Peripheral blood mononuclear cell ,Article ,law.invention ,Zidovudine ,Medicinal and Biomolecular Chemistry ,Drug Delivery Systems ,law ,medicine ,Leukocytes ,Nanotechnology ,Humans ,Vault (organelle) ,Cells, Cultured ,Ribonucleoprotein ,Pharmacology ,Cultured ,010405 organic chemistry ,Chemistry ,Elvitegravir ,Organic Chemistry ,021001 nanoscience & nanotechnology ,Virology ,0104 chemical sciences ,Drug Liberation ,Infectious Diseases ,Targeted drug delivery ,Anti-Retroviral Agents ,Ribonucleoproteins ,5.1 Pharmaceuticals ,Recombinant DNA ,HIV-1 ,Leukocytes, Mononuclear ,HIV/AIDS ,Nanoparticles ,Biochemistry and Cell Biology ,0210 nano-technology ,Infection ,medicine.drug ,Biotechnology - Abstract
"Vaults" are ubiquitously expressed endogenous ribonucleoprotein nanoparticles with potential utility for targeted drug delivery. Here, we show that recombinant human vault nanoparticles are readily engulfed by certain key human peripheral blood mononuclear cells (PBMC), predominately dendritic cells, monocytes/macrophages, and activated T cells. As these cell types are the primary targets for human immunodeficiency virus type 1 (HIV-1) infection, we examined the utility of recombinant human vaults for targeted delivery of antiretroviral drugs. We chemically modified three different antiretroviral drugs, zidovudine, tenofovir, and elvitegravir, for direct conjugation to vaults. Tested in infection assays, drug-conjugated vaults inhibited HIV-1 infection of PBMC with equivalent activity to free drugs, indicating vault delivery and drug release in the cytoplasm of HIV-1-susceptible cells. The ability to deliver functional drugs via vault nanoparticle conjugates suggests their potential utility for targeted drug delivery against HIV-1.
- Published
- 2019
43. Suboptimal stimulation by weak agonist epitope variants does not drive dysfunction of HIV-1-specific cytotoxic T lymphocyte clones
- Author
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Otto O. Yang, Christian Hofmann, Mark A Grossman, and Hwee L. Ng
- Subjects
0301 basic medicine ,HIV Antigens ,medicine.medical_treatment ,Immunology ,Epitopes, T-Lymphocyte ,Stimulation ,Biology ,Epitope ,Article ,03 medical and health sciences ,0302 clinical medicine ,Gene expression ,medicine ,Immunology and Allergy ,Cytotoxic T cell ,Humans ,030212 general & internal medicine ,Cytotoxicity Tests, Immunologic ,CTL ,030104 developmental biology ,Infectious Diseases ,Cytokine ,Apoptosis ,HIV-1 ,Cytokines ,Cytokine secretion ,T-Lymphocytes, Cytotoxic - Abstract
OBJECTIVE: To assess whether weakly recognized epitope variants induce anergy in HIV-1-specific CD8(+) T lymphocyte (CTL) clones as a mechanism of dysfunction. DESIGN: HIV-1-specific CTL clones were exposed to suboptimally recognized epitope variants, and screened for anergy and other T cell dysfunction markers, and subsequent capability to kill target cells bearing index epitope. METHODS: In addition to the optimally recognized index epitope, two suboptimally recognized epitope variants were selected based on titration curves for killing of peptide-labeled target cells by three HIV-1-specific CTL clones targeting the epitopes SLYNTVATL (Gag 77-85, A*02-restricted), RPAEPVPLQL (Rev 66-75, B*07-restricted), and KRWIIMGLNK (Gag 263-272, B*27-restricted). Consequences of suboptimal stimulation were assessed by cytokine secretion, gene expression, and capacity to kill index epitope-labeled target cells upon rechallenge. RESULTS: Suboptimal recognition of epitope variants reduced cytokine production by CTL similarly to reduction in killing of target cells. Gene expression profiles after suboptimal stimulation demonstrated no patterns consistent with T cell dysfunction due to anergy, exhaustion, or apoptosis. Pre-exposure of CTL to epitope variants had no discernable impact on their subsequent capacity to kill index epitope-bearing target cells. CONCLUSIONS: Our data explore the hypothesis that poorly recognized epitope variants not only facilitate HIV-1 evasion of CTL recognition, but also induce CTL dysfunction through suboptimal signaling causing anergy. However, the results do not suggest that suboptimal signaling induces anergy (or exhaustion or apoptosis), indicating that the major role of CTL epitope variation is likely viral escape.
- Published
- 2019
44. Nef-induced differential gene expression in primary CD4+ T cells following infection with HIV-1 isolates
- Author
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Otto O. Yang, Ayub Ali, Douglas F. Nixon, and Robert L. Furler
- Subjects
CD4-Positive T-Lymphocytes ,Gene Expression Regulation, Viral ,viruses ,Priming (immunology) ,Ribosome biogenesis ,Biology ,Virus Replication ,Virus ,Article ,03 medical and health sciences ,Interferon ,Virology ,Gene expression ,Genetics ,medicine ,Humans ,nef Gene Products, Human Immunodeficiency Virus ,Molecular Biology ,Gene ,Cells, Cultured ,030304 developmental biology ,0303 health sciences ,030306 microbiology ,virus diseases ,General Medicine ,Cell cycle ,Viral replication ,HIV-1 ,medicine.drug - Abstract
Almost 80% of viral transcripts during early HIV-1 infection encode the Nef protein, which has been implicated in altering expression of a number of genes. In this study, we infected primary human CD4+ T cells with pseudotyped Nef-containing or Nef-deleted (Δ-nef) NL4-3 virus and used RNA-Sequencing (RNA-Seq) for transcriptomic analysis. Our results showed that the interferon response, IL-15 and JAK/STAT signaling, as well as genes involved in metabolism, apoptosis, cell cycle regulation, and ribosome biogenesis were all altered in the presence of Nef. These early Nef-mediated transcriptional alterations may play a role in priming the host cell for cellular activation and viral replication.
- Published
- 2019
45. A Flow Cytometric Method to Determine Transfection Efficiency
- Author
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Otto O. Yang, Theodoros Kelesidis, Wenli Mu, Stefanie Homann, Diana Huynh, Alexandr Gorin, and Christian Hofmann
- Subjects
animal structures ,viruses ,Strategy and Management ,Bioengineering ,Transfection ,Article ,Industrial and Manufacturing Engineering ,Flow cytometry ,Single-cell analysis ,Genetics ,medicine ,DNA labeling ,Gene ,medicine.diagnostic_test ,Chemistry ,Mechanical Engineering ,fungi ,Metals and Alloys ,RNA ,Cell biology ,Nucleic acids ,embryonic structures ,Nucleic acid ,Protein expression ,Exogenous DNA ,Target protein ,Biotechnology - Abstract
Mammalian cell transfection is a powerful technique commonly used in molecular biology to express exogenous DNA or RNA in cells and study gene and protein function. Although several transfection strategies have been developed, there is a wide variation with regards to transfection efficiency, cell toxicity and reproducibility. Thus, a sensitive and robust method that can optimize transfection efficiency based not only on expression of the target protein of interest but also on the uptake of the nucleic acids, can be an important tool in molecular biology. Herein, we present a simple, rapid and robust flow cytometric method that can be used as a tool to optimize transfection efficiency while overcoming limitations of prior established methods that quantify transfection efficiency.
- Published
- 2019
46. HIV-1-Specific Chimeric Antigen Receptors Based on Broadly Neutralizing Antibodies
- Author
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Scott G. Kitchen, Jerome A. Zack, Otto O. Yang, Hwee L. Ng, Ayub Ali, and Irvin S. Y. Chen
- Subjects
0301 basic medicine ,T-Lymphocytes ,medicine.medical_treatment ,Immunology ,HIV Infections ,HIV Antibodies ,Biology ,Microbiology ,Jurkat cells ,Virus ,Jurkat Cells ,03 medical and health sciences ,Receptors, HIV ,0302 clinical medicine ,Virology ,medicine ,Humans ,Amino Acid Sequence ,Sequence Homology, Amino Acid ,Antibodies, Monoclonal ,Immunotherapy ,Antibodies, Neutralizing ,Chimeric antigen receptor ,Receptors, Antigen ,030104 developmental biology ,Viral replication ,030220 oncology & carcinogenesis ,Insect Science ,HIV-1 ,biology.protein ,Pathogenesis and Immunity ,Antibody ,human activities ,Single-Chain Antibodies ,Binding domain - Abstract
Although the use of chimeric antigen receptors (CARs) based on single-chain antibodies for gene immunotherapy of cancers is increasing due to promising recent results, the earliest CAR therapeutic trials were done for HIV-1 infection in the late 1990s. This approach utilized a CAR based on human CD4 as a binding domain and was abandoned for a lack of efficacy. The growing number of HIV-1 broadly neutralizing antibodies (BNAbs) offers the opportunity to generate novel CARs that may be more active and revisit this modality for HIV-1 immunotherapy. We used sequences from seven well-defined BNAbs varying in binding sites and generated single-chain-antibody-based CARs. These CARs included 10E8, 3BNC117, PG9, PGT126, PGT128, VRC01, and X5. Each novel CAR exhibited conformationally relevant expression on the surface of transduced cells, mediated specific proliferation and killing in response to HIV-1-infected cells, and conferred potent antiviral activity (reduction of viral replication in log 10 units) to transduced CD8 + T lymphocytes. The antiviral activity of these CARs was reproducible but varied according to the strain of virus. These findings indicated that BNAbs are excellent candidates for developing novel CARs to consider for the immunotherapeutic treatment of HIV-1. IMPORTANCE While chimeric antigen receptors (CARs) using single-chain antibodies as binding domains are growing in popularity for gene immunotherapy of cancers, the earliest human trials of CARs were done for HIV-1 infection. However, those trials failed, and the approach was abandoned for HIV-1. The only tested CAR against HIV-1 was based on the use of CD4 as the binding domain. The growing availability of HIV-1 broadly neutralizing antibodies (BNAbs) affords the opportunity to revisit gene immunotherapy for HIV-1 using novel CARs based on single-chain antibodies. Here we construct and test a panel of seven novel CARs based on diverse BNAb types and show that all these CARs are functional against HIV-1.
- Published
- 2016
47. Highly Attenuated Infection With a Vpr-Deleted Molecular Clone of Human Immunodeficiency Virus-1
- Author
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Joel N. Blankson, Brian Moldt, Ayub Ali, Jonathan Fulcher, Hwee L. Ng, Dennis R. Burton, Robert W. Buckheit, Otto O. Yang, F. Javier Ibarrondo, and Peter A. Anton
- Subjects
0301 basic medicine ,viruses ,Clone (cell biology) ,HIV Infections ,CD8-Positive T-Lymphocytes ,Macaque ,Medical and Health Sciences ,Immunology and Allergy ,2.1 Biological and endogenous factors ,Cloning, Molecular ,Aetiology ,Neutralizing antibody ,AIDS Vaccines ,B-Lymphocytes ,Vaccines ,Vaccination ,virus diseases ,Middle Aged ,Biological Sciences ,Infectious Diseases ,HIV/AIDS ,Female ,Infection ,Viremia ,Biology ,Vaccines, Attenuated ,Microbiology ,Vaccine Related ,03 medical and health sciences ,Major Articles and Brief Reports ,Immune system ,biology.animal ,medicine ,Humans ,Gene Products ,Seroconversion ,Vaccine Related (AIDS) ,Gene Products, vpr ,Prevention ,Molecular ,vpr ,medicine.disease ,Virology ,030104 developmental biology ,Attenuated ,Good Health and Well Being ,elite control ,biology.protein ,HIV-1 ,Immunization ,CD8 ,Cloning - Abstract
A 48-year-old woman was infected with a vpr-defective human immunodeficiency virus (HIV)-1 molecular clone. Seroconversion was markedly delayed, and without treatment she had durably suppressed viremia and normal T-cell levels. Neutralizing antibody and CD8(+) T-cell immune responses against HIV-1 were unremarkable. Viral sequences confirmed the source but evolved defective nef, suggesting an unknown mechanistic link to vpr. There were subtle qualitative defects in T and B cells. To our knowledge, this is the only case of human infection with a characterized defective HIV-1 molecular clone, which furthermore recapitulated live-attenuated vaccination in macaque models of HIV-1 vaccine research.
- Published
- 2018
48. Cross-Reactivity against Multiple HIV-1 Epitopes Is Characteristic of HIV-1-Specific Cytotoxic T Lymphocyte Clones
- Author
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Otto O. Yang, Arumugam Balamurugan, Hwee L. Ng, and Silvestri, Guido
- Subjects
0301 basic medicine ,Cellular immunity ,Cytotoxic ,cross-reactivity ,T-Lymphocytes ,Epitopes, T-Lymphocyte ,HIV Infections ,cytotoxic T lymphocyte ,medicine.disease_cause ,Cross-reactivity ,Medical and Health Sciences ,Epitope ,Epitopes ,0302 clinical medicine ,Cytotoxic T cell ,Cells, Cultured ,Heterologous ,Cultured ,biology ,Biological Sciences ,Infectious Diseases ,HIV/AIDS ,Infection ,Genotype ,Cells ,Immunology ,chemical and pharmacologic phenomena ,Cross Reactions ,Major histocompatibility complex ,Immunity, Heterologous ,Microbiology ,Vaccine Related ,03 medical and health sciences ,Immune system ,Virology ,medicine ,Humans ,Avidity ,Author Correction ,Agricultural and Veterinary Sciences ,Prevention ,Inflammatory and immune system ,Histocompatibility Antigens Class I ,Immunity ,HIV ,CTL ,030104 developmental biology ,Good Health and Well Being ,T-Lymphocyte ,Insect Science ,biology.protein ,HIV-1 ,Pathogenesis and Immunity ,Immunization ,030215 immunology ,T-Lymphocytes, Cytotoxic - Abstract
Although a high level of promiscuity for heterologous epitopes is believed to exist for cellular immunity, limited data explore this issue for human immunodeficiency virus type 1 (HIV-1)-specific CD8+ T lymphocyte (CTL) responses. Here, we found an unexpected degree of heterologous cross-reactivity against HIV-1 epitopes, in addition to the targeted index epitope. Most CTL clones screened cross-reacted against other known HIV-1 epitopes of the same major histocompatibility complex type I (MHC-I) restriction, up to 40% of tested nonindex epitopes in some cases. The observed cross-reactivity was universally lower avidity than recognition of the index epitope when examined for several A*02- and B*57-restricted CTL clones, demonstrating that the high concentrations of exogenous epitope typically used for screening of CTL responses are prone to detect such cross-reactivity spuriously. In agreement with this, we found that these cross-reactive responses do not appear to mediate CTL activity against HIV-1-infected cells. Overall, our data indicate that low-level cross-reactivity is remarkably common for HIV-1-specific CTLs. The role of this phenomenon is unclear, but low-avidity interactions have been shown to foster homeostatic proliferation of memory T cells.IMPORTANCE This study raises two issues related to HIV-1-specific CTL responses. These are key immune responses that retard disease progression in infected persons that are highly relevant to immunotherapies and vaccines for HIV-1. First, we make the novel observation that these responses are promiscuous and that CTLs targeting one epitope may cross-recognize other, completely distinct epitopes in the virus. While these are low-avidity interactions that do not appear to contribute directly to the antiviral activity of CTLs, this raises interesting biologic implications regarding the purpose of the phenomenon, such as providing a stimulus for these responses to persist long term. Second, the data raise a technical caveat to detection of CTL responses against particular epitopes, suggesting that some methodologies may unintentionally detect cross-reactivity and overestimate responses against an epitope.
- Published
- 2018
49. Brief Report: Changes in Plasma RANKL-Osteoprotegerin in a Prospective, Randomized Clinical Trial of Initial Antiviral Therapy: A5260s
- Author
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Elizabeth Johnston, Todd T. Brown, Theodoros Kelesidis, Michael P. Dubé, Judith S. Currier, James H. Stein, Carlee Moser, Otto O. Yang, and Grace A. McComsey
- Subjects
0301 basic medicine ,musculoskeletal diseases ,Adult ,Male ,medicine.medical_specialty ,Bone disease ,Urology ,HIV Infections ,Article ,03 medical and health sciences ,0302 clinical medicine ,Osteoprotegerin ,Blood plasma ,medicine ,Humans ,Pharmacology (medical) ,030212 general & internal medicine ,Prospective Studies ,Prospective cohort study ,Bone mineral ,biology ,business.industry ,RANK Ligand ,Middle Aged ,medicine.disease ,030112 virology ,Atazanavir ,Infectious Diseases ,RANKL ,biology.protein ,Ritonavir ,Female ,business ,medicine.drug - Abstract
BACKGROUND: The contributions of the Receptor activator of nuclear factor kappa-B ligand (RANKL)/osteoprotegerin (OPG) axis to cardiovascular and bone disease in treated HIV-1 infection is not well-defined. SETTING: Prospective, observational, longitudinal study. METHODS: In a subset analysis of a prospective randomized clinical trial, 234 HIV-1-infected antiretroviral therapy (ART)-naïve participants received tenofovir-emtricitabine plus either atazanavir/ritonavir, darunavir/ritonavir, or raltegravir and achieved plasma HIV-1 RNA
- Published
- 2018
50. Detecting the Prevalence of Chagas Disease among People Living with HIV/AIDS in Los Angeles County, California
- Author
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Adam Carl Sukhija-Cohen, Tyler Evans, Leonardo Colemon, Selena P Than, and Otto O Yang
- Subjects
0301 basic medicine ,Chagas disease ,03 medical and health sciences ,Acquired immunodeficiency syndrome (AIDS) ,business.industry ,Environmental health ,030106 microbiology ,medicine ,medicine.disease ,business - Published
- 2018
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