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The ability to reconstitute a normal immune system with antiretroviral therapy in the setting of HIV infection remains uncertain. This study aimed to characterize quantitative and qualitative aspects of various T cell subpopulations that do not improve des

Background: Although untreated human immunodeficiency virus (HIV)-infected patients maintaining undetectable plasma HIV RNA levels (elite controllers) have high HIV-specific immune responses, it is unclear whether they experience abnormal levels of T cell activation, potentially contributing to immunodeficiency.Methods: We compared percentages of activated (CD38(+)HLA-DR(+)) T cells between 30 elite controllers, 47 HIV-uninfected individuals, 187 HIV-infected individuals with undetectable viremia receiving antiretroviral therapy (antiretroviral therapy suppressed), and 66 untreated HIV-infected individuals with detectable viremia. Because mucosal translocation of bacterial products may contribute to T cell activation in HIV infection, we also measured plasma lipopolysaccharide (LPS) levels.Results: Although the median CD4(+) cell count in controllers was 727 cells/mm(3), 3 (10%) had CD4(+) cell counts <350 cells/mm(3) and 2 (7%) had acquired immunodeficiency syndrome. Controllers had higher CD4(+) and CD8(+) cell activation levels (P < .001 for both) than HIV-negative subjects and higher CD8(+) cell activation levels than the antiretroviral therapy suppressed (P = .048). In controllers, higher CD4(+) and CD8(+) T cell activation was associated with lower CD4(+) cell counts (P = .009 and P = .047). Controllers had higher LPS levels than HIV-negative subjects (P < .001), and in controllers higher LPS level was associated with higher CD8(+) T cell activation (P = .039).Conclusion: HIV controllers have abnormally high T cell activation levels, which may contribute to progressive CD4(+) T cell loss even without measurable viremia. [ABSTRACT FROM AUTHOR]

Abstract Background Diminished IL-2 production and lack of effector differentiation have been reported for HIV-specific T cells. In this study, we examined the prevalence of these phenomena using 8-color cytokine flow cytometry, and tested the hypothesis that these two findings were causally related. We analyzed cytokine profiles and memory/effector phenotypes of HIV-specific and CMV-specific T cells using short-term in vitro stimulation with HIV or CMV peptide pools. Nineteen HIV-positive subjects with progressive disease and twenty healthy, HIV-negative subjects were examined. Results Among HIV-infected subjects, there were significantly fewer CD8+ IL-2+ T cells responding to HIV compared to CMV, with no significant difference in CD4+ IL-2+ T cells. The majority of CMV-specific T cells in both HIV-negative and HIV-positive subjects appeared to be terminally differentiated effector cells (CD8+ CD27- CD28- CD45RA+ or CD8+ CD27- CD28- CD45RA-). In HIV-positive subjects, the most common phenotype of HIV-specific T cells was intermediate in differentiation (CD8+ CD27+ CD28- CD45RA-). These differences were statistically significant, both as absolute cell frequencies and as percentages. There was a significant correlation between the absolute number of HIV-specific CD8+ IL-2+ T cells and HIV-specific CD8+ CD27- CD28- CD45RA+ terminal effector cells. Conclusion IL-2 production from antigen-specific CD8+ T cells correlates with effector cell differentiation of those cells.

Patients undergoing antineoplastic therapies often exhibit reduced immune response to COVID-19 vaccination, necessitating assessment of alternate booster vaccination frequencies. However, data on reinfection risks to guide clinical decision making are limited. Here, we quantified reinfection risks for patients undergoing distinct antineoplastic therapies, given alternative frequencies of boosting with Pfizer-BioNTech BNT162b2. Integrating antibody data following vaccination with long-term antibody data from other coronaviruses in an evolutionary framework, we estimated infection probabilities based on antibody levels and calculated cumulative probabilities of breakthrough infection for alternate booster schedules over 2 years. Annual boosting reduced risks for targeted or hormonal treatments, immunotherapy, and chemotherapy-immunotherapy combinations similarly to the general population. Patients receiving no treatment or chemotherapy exhibited higher risks, suggesting that accelerated vaccination schedules should be considered. Patients treated with rituximab therapy presented the highest infection risk, suggesting that a combination of frequent boosting and additional interventions may be warranted for mitigating SARS-CoV-2 infection., (© The Author(s) 2023. Published by Oxford University Press.)

CD8 + T cells are essential components of the immune response against viral infections and tumours, and are capable of eliminating infected and cancerous cells. However, when the antigen cannot be cleared, T cells enter a state known as exhaustion 1 . Although it is clear that chronic antigen contributes to CD8 + T cell exhaustion, less is known about how stress responses in tissues regulate T cell function. Here we show a new link between the stress-associated catecholamines and the progression of T cell exhaustion through the β 1 -adrenergic receptor ADRB1. We identify that exhausted CD8 + T cells increase ADRB1 expression and that exposure of ADRB1 + T cells to catecholamines suppresses their cytokine production and proliferation. Exhausted CD8 + T cells cluster around sympathetic nerves in an ADRB1-dependent manner. Ablation of β 1 -adrenergic signalling limits the progression of T cells towards the exhausted state in chronic infection and improves effector functions when combined with immune checkpoint blockade (ICB) in melanoma. In a pancreatic cancer model resistant to ICB, β-blockers and ICB synergize to boost CD8 + T cell responses and induce the development of tissue-resident memory-like T cells. Malignant disease is associated with increased catecholamine levels in patients 2,3 , and our results establish a connection between the sympathetic stress response, tissue innervation and T cell exhaustion. Here, we uncover a new mechanism by which blocking β-adrenergic signalling in CD8 + T cells rejuvenates anti-tumour functions., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

In response to longstanding healthcare inequities unmasked by the Coronavirus Disease 2019 pandemic, the infectious diseases (ID) section at the Yale School of Medicine designed and implemented a pilot curriculum integrating Infectious Disease Diversity, Equity, and Antiracism (ID2EA) into ID educational training and measured program outcomes. We herein describe a mixed-methods assessment of section members on whether the ID2EA curriculum affected their beliefs and behaviors regarding racism and healthcare inequities. Participants rated the curriculum as useful (92% averaging across sessions) and effective in achieving stated learning objectives (89% averaging across sessions), including fostering understanding of how inequities and racism are linked to health disparities and identifying strategies to effectively deal with racism and inequities. Despite limitations in response rates and assessment of longer-term behavioral change, this work demonstrates that training in diversity, equity, and antiracism can be successfully integrated into ID physicians' educational activities and affect physicians' perspectives on these topics., Competing Interests: Potential conflicts of interest. S. E. G. reports that the Yale School of Medicine Department of Internal Medicine awarded an $5000 educational research grant to the ID2EA committee. This award is to expand the curriculum and work of the committee, and none of the funding goes directly to committee members. B. E. reports consulting fees from and participation on data safety monitoring or advisory board for Theratechnologies (treatment-experienced human immunodeficiency virus [HIV] and HIV and liver disease). M. P. G. reports payment or honoraria from Health Monitor Network for contributing to an article (payment to author) and participation as a data safety monitoring board member for Universidade Federal de Minas Gerais (use of methotrexate for treatment of chikungunya arthritis in Brazil). J. P. M. reports grants or contracts to institution from the National Institute on Drug Abuse, National Institute of Mental Health, National Institute of Allergy and Infectious Diseases, and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, the Substance Abuse and Mental Health Services Administration, the Doris Duke Charitable Foundation, and Gilead Science; consulting fees to author from the National Institute on Drug Abuse; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events to author from the Opioid Response Network, the National Institutes of Health grant review, the Doris Duke Charitable Foundation grant review, University of Massachusetts Worcester, and the New England AIDS Education and Training Center; payment for expert testimony to author from Budge and Heipt, Yale Law School, Munger, Tolles & Olson, LLP, Baltimore CDF, Silver Golub & Teitell, and the Lawyers’ Committee for Civil Rights Under Law (John Fowler). J. R. reports an unpaid role as chair of the Advocacy Committee for the History of Science Society. S. V. S. reports that her spouse worked for Merck Pharmaceuticals from 1997 to 2007 and retains stock in a retirement account (no conflict of interest regarding the current work but included for full disclosure). M. V. reports HRSA-22-028 (HIV and aging Special Projects of National Significance grant) from Yale University and the Connecticut Department of Public Health (Ryan White Part B funding) from Yale–New Haven Hospital; personal consulting fees from ViiV Healthcare, Gilead Sciences, and Janssen Pharmaceuticals; personal payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from the CT AIDS Education and Training Center and Northeast AIDS Education and Training Center; support for attending meetings and/or travel from Yale University for the Conference on Retroviruses and Opportunistic Infections and from the CT State Medical Society for American Medical Association national meetings; noncompensated roles as president of the New Haven County Medical Association, a board member for Project Access New Haven, and a council member for the CT State Medical Society; stock or stock options within retirement funds; and other personal financial or nonfinancial interests in Healthline and Guidepoint. M. S. D. reports roles as president and past president of American Committee of Molecular, Cellular, and Immunoparasitology subgroup of the American Society of Tropical Medicine and Hygiene. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: Compared with people living without HIV (PWOH), people living with HIV (PWH) and cancer have traditionally been excluded from immune checkpoint inhibitor (ICI) trials. Furthermore, there is a paucity of real-world data on the use of ICIs in PWH and cancer., Methods: This retrospective study included PWH treated with anti-PD-1- or anti-PD-L1-based therapies for advanced cancers. Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS). Objective response rates (ORRs) were measured per RECIST 1.1 or other tumor-specific criteria, whenever feasible. Restricted mean survival time (RMST) was used to compare OS and PFS between matched PWH and PWOH with metastatic NSCLC (mNSCLC)., Results: Among 390 PWH, median age was 58 years, 85% (n = 331) were males, 36% (n = 138) were Black; 70% (n = 274) received anti-PD-1/anti-PD-L1 monotherapy. Most common cancers were NSCLC (28%, n = 111), hepatocellular carcinoma ([HCC]; 11%, n = 44), and head and neck squamous cell carcinoma (HNSCC; 10%, n = 39). Seventy percent (152/216) had CD4+ T cell counts ≥200 cells/µL, and 94% (179/190) had HIV viral load <400 copies/mL. Twenty percent (79/390) had any grade immune-related adverse events (irAEs) and 7.7% (30/390) had grade ≥3 irAEs. ORRs were 69% (nonmelanoma skin cancer), 31% (NSCLC), 16% (HCC), and 11% (HNSCC). In the matched mNSCLC cohort (61 PWH v 110 PWOH), 20% (12/61) PWH and 22% (24/110) PWOH had irAEs. Adjusted 42-month RMST difference was -0.06 months (95% CI, -5.49 to 5.37; P = .98) for PFS and 2.23 months (95% CI, -4.02 to 8.48; P = .48) for OS., Conclusion: Among PWH, ICIs demonstrated differential activity across cancer types with no excess toxicity. Safety and activity of ICIs were similar between matched cohorts of PWH and PWOH with mNSCLC.

Background: Head and neck squamous cell cancer (HNSCC) occurs at higher rates among persons with HIV (PWH). This study compares the impact of sociodemographic and clinicopathologic characteristics on outcomes among PWH-HNSCC compared with HNSCC patients without HIV., Methods: Patient data from HNSCC individuals were collected at a single academic hospital center between 2002 and 2018. Forty-eight patients with HIV (HIV-HNSCC) and 2894 HNSCC patients without HIV were included. Multivariate analysis determined predictors of survival using Cox proportional hazards regression model. HIV-positive and -negative tumors were analyzed by quantitative immunofluorescence for expression of CD4, CD8, CD20 and PD-L1., Results: HIV-HNSCC patients had a lower median overall survival than HNSCC patients without HIV (34 [18-84] vs 94 [86-103] months; P < .001). In multivariate analysis that included age, sex, race/ethnicity, stage, site, tobacco use, time to treatment initiation, and insurance status, HIV was an independent predictor of poorer survival, with a hazard ratio of 1.98 (95% CI: 1.32-2.97; P < .001). PWH with human papillomavirus (HPV)-positive oropharyngeal tumors also had worse prognosis than HPV-positive oropharyngeal tumors in the population without HIV (P < .001). The tumor microenvironment among HIV-HNSCC patients revealed lower intratumoral CD8 infiltration among HIV+ HPV+ tumors compared with HIV- HPV+ tumors (P = .04)., Conclusions: HIV-HNSCC patients had worse prognosis than the non-HIV population, with HIV being an independent predictor of poor clinical outcomes when accounting for important sociodemographic and clinicopathologic factors. Our findings highlight differences in tumor biology that require further detailed characterization in large cohorts and increased inclusion of PWH in immunotherapy trials., Competing Interests: Potential conflicts of interest. B. E. reports consulting fees from Theratechnologies and Genentech/Roche unrelated to this work; participation on an Advisory Board for Theratechnologies unrelated to this work; and stock or stock options with Bausch Health Companies and Bristol Myers Squibb. G. G. reports support unrelated to this work from the Yale Transplant Group (author works as a statistician working at the Yale Center for Analytical Sciences; part of the author's effort is covered by Yale Transplant for providing statistical support for their research studies). K. A. S. reports grants or contracts unrelated to this work from Navigate Biopharma, Tesaro/GSK, Moderna, Inc, Takeda, Surface Oncology, Pierre-Fabre Research Institute, Merck, Bristol-Myers Squibb, AstraZeneca, Ribon Therapeutics, Eli Lilly, Boehringer-Ingelheim, and Akoya Biosciences (all contracted to Yale University); consulting fees paid to the author from Clinica Alemana Santiago, Shattuck Labs, Genmab, AstraZeneca, EMD Serono, Takeda, Torque/Repertoire Therapeutics, Takeda, Agenus, Genmab, OnCusp, Parthenon Therapeutics, Bristol-Myers Squibb, Roche, CDR Life, Sensei Therapeutics, Molecular Templates, and Merck; payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing, or educational events from PeerView, Forefront Collaborative, Merck; payment for expert testimony from AstraZeneca; and support for attending meetings and/or travel from Fluidigm. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: CD4/CD8 ratio is a marker of immune activation in HIV infection and has been associated with neurocognitive performance during chronic infection, but little is known about the early phases. The aim of this study was to examine the relationship between blood CD4/CD8 ratio and central nervous system endpoints in primary HIV infection (PHI) before and after antiretroviral treatment (ART)., Methods: This was a retrospective analysis of the Primary Infection Stage CNS Events Study (PISCES) cohort. We longitudinally assessed blood and cerebrospinal fluid (CSF) markers of inflammation, immune activation and neuronal injury, and neuropsychological testing performance (NPZ4, an average of three motor and one processing speed tests, and a summarized total score, NPZ11, including also executive function, learning and memory) in ART-naïve participants enrolled during PHI. Spearman correlation and linear mixed models assessed the relationships between the trajectory of CD4/CD8 ratio over time and neurocognitive performance, blood and CSF markers of immune activation and neuronal injury., Results: In all, 109 PHI participants were enrolled. The mean CD4/CD8 ratio decreased with longer time from infection to starting treatment (p < 0.001). Every unit increase in NPZ4 score was independently associated with a 0.15 increase in CD4/CD8 ratio (95% CI: 0.002-0.29; p = 0.047), whereas no correlation was found between CD4/CD8 ratio and NPZ11. Among the cognitive domains, only a change in processing speed was correlated with CD4/CD8 ratio over time (p = 0.03). The trajectory of the CD4/CD8 ratio was negatively correlated with change in CSF neurofilament light chain (p = 0.04)., Conclusions: The trajectory of CD4/CD8 ratio was independently associated with motor/psychomotor speed performance, suggesting that immune activation is involved in brain injury during the early stages of the infection., (© 2022 British HIV Association.)

Background: We studied whether comorbid conditions affect strength and duration of immune responses after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) messenger RNA vaccination in a US-based, adult population., Methods: Sera (before and after BNT162b2 vaccination) were tested serially up to 12 months after 2 doses of vaccine for SARS-CoV-2-anti-Spike neutralizing capacity by pseudotyping assay in 124 individuals; neutralizing titers were correlated to clinical variables with multivariate regression. Postbooster (third dose) effect was measured at 1 and 3 months in 72 and 88 subjects, respectively., Results: After completion of primary vaccine series, neutralizing antibody half maximal inhibitory concentration (IC50) values were high at 1 month (14-fold increase from prevaccination), declined at 6 months (3.3-fold increase), and increased at 1 month postbooster (41.5-fold increase). Three months postbooster, IC50 decreased in coronavirus disease (COVID)-naïve individuals (18-fold increase) and increased in prior COVID 2019 (COVID-19+) individuals (132-fold increase). Age >65 years (β = -0.94, P = .001) and malignancy (β = -0.88, P = .002) reduced strength of response at 1 month. Both neutralization strength and durability at 6 months, respectively, were negatively affected by end-stage renal disease ([β = -1.10, P = .004]; [β = -0.66, P = .014]), diabetes mellitus ([β = -0.57, P = .032]; [β = -0.44, P = .028]), and systemic steroid use ([β = -0.066, P = .032]; [β = -0.55, P = .037]). Postbooster IC50 was robust against WA-1 and B.1.617.2. Postbooster neutralization increased with prior COVID-19 (β = 2.9, P < .0001), and malignancy reduced neutralization response (β = -0.68, P = .03), regardless of infection status., Conclusions: Multiple clinical factors affect the strength and duration of neutralization response after primary series vaccination, but not the postbooster dose strength. Malignancy was associated with lower booster-dose response regardless of prior COVID infection, suggesting a need for clinically guided vaccine regimens., Competing Interests: Potential conflicts of interest. None of the authors declare any conflict of interests: Q. S. reports support for the present manuscript from VA Connecticut Research and Education Foundation. E. M. and S. G. report being members of IRB committee at West Haven VA, recused themselves during discussion of study. R. S. reports support for the present manuscript from WHVA Research Service and serving on DSMB for Moderna for several clinical mRNA vaccine studies. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2022.)

T cell-B cell interaction is the key immune response to protect the host from severe viral infection. However, how T cells support B cells to exert protective humoral immunity in humans is not well understood. Here, we use COVID-19 as a model of acute viral infections and analyze CD4 + T cell subsets associated with plasmablast expansion and clinical outcome. Peripheral helper T cells (Tph cells; denoted as PD-1 high CXCR5 - CD4 + T cells) are significantly increased, as are plasmablasts. Tph cells exhibit "B cell help" signatures and induce plasmablast differentiation in vitro. Interestingly, expanded plasmablasts show increased CXCR3 expression, which is positively correlated with higher frequency of activated Tph cells and better clinical outcome. Mechanistically, Tph cells help B cell differentiation and produce more interferon γ (IFNγ), which induces CXCR3 expression on plasmablasts. These results elucidate a role for Tph cells in regulating protective B cell response during acute viral infection., Competing Interests: Declaration of interests D.A.H. has received research funding from Bristol-Myers Squibb, Novartis, Sanofi, and Genentech. He has been a consultant for Bayer Pharmaceuticals, Bristol Myers Squibb, Compass Therapeutics, EMD Serono, Genentech, Juno Therapeutics, Novartis Pharmaceuticals, Proclara Biosciences, Sage Therapeutics, and Sanofi Genzyme. Further information regarding funding is available at https://openpaymentsdata.cms.gov/physician/166753/general-payments. N.K. reports personal fees from Boehringer Ingelheim, Third Rock, Pliant, Samumed, NuMedii, Indalo, Theravance, LifeMax, Three Lake Partners, and RohBar in the last 36 months and Equity in Pliant. N.K. is also a recipient of a grant from Veracyte and non-financial support from Miragen. In addition, N.K. has patents on New Therapies in Pulmonary Fibrosis and ARDS (unlicensed) and Peripheral Blood Gene Expression as biomarkers in IPF (licensed to biotech), all outside the submitted work. S.H.K. receives consulting fees from Northrop Grumman. K.B.H. receives consulting fees from Prellis Biologics., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Alterations in the components of the immune system occur with aging. The introduction of combination antiretroviral therapy (ART) has dramatically improved life expectancy in human immunodeficiency virus (HIV) infected individuals by suppressing viral replication and increasing CD4 + T-cell counts. Immunosenescence-like changes, including the expansion of memory CD8 + T cells with senescent features, are reported in young HIV-infected individuals who do not have clinically detectable viremia on ART. However, it is less known whether HIV infection affects the immunosenescent status in older HIV-infected individuals. Here, we addressed this question in older HIV-infected, HIV-uninfected, and frail individuals (all groups age ≥65 years) by examining a set of aging-associated genes in peripheral blood mononuclear cells (PBMCs) as well as by analyzing subsets of CD4 + and CD8 + T cells in depth using high-dimensional CyTOF analysis. Older HIV-infected individuals had increased expression of aging-associated genes such as CX3CR1 in PBMCs which are related to IL-7 receptor low effector memory (IL-7Rα low EM) CD8 + T cells, a cell population known to expand with age. The subsets of IL-7Rα low EM CD8 + T cells expressing senescent, cytotoxic, and inflammatory molecules, including CD57, perforin, and CX3CR1, as well as memory CD4 + T cells expressing CD161 and CXCR3, molecules associated with replication-competent HIV-1 harboring cells, were increased in older HIV-infected individuals. Overall, older HIV-infected individuals without detectable viremia on ART had augmented levels of age-associated immune alterations in PBMCs, suggesting that HIV infection has a persistent impact on senescence in older HIV-infected individuals despite the clinically controlled viremia., (© 2022 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Introduction: Entry inhibitors are a relatively new class of antiretroviral therapy and are typically indicated in heavily treatment experienced individuals living with HIV. Despite this, there is no formal definition of 'heavily treatment experienced'. Interpretation of this term generally includes acknowledgement of multidrug resistance and reflects the fact that patients in need of further treatment options may have experienced multiple lines of therapy. However, it fails to recognize treatment limiting factors including contraindications, age-associated comorbidities, and difficulty adhering to regimens., Methods: This manuscript follows a roundtable discussion and aims to identify the unmet needs of those living with HIV who are in need of further treatment options, to broaden the definition of heavily treatment experienced and to clarify the use of newer agents, with an emphasis on the potential role of entry inhibitors, in this population., Results/conclusions: Within the entry inhibitor class, mechanisms of action differ between agents; resistance to one subclass does not confer resistance to others. Combinations of entry inhibitors should be considered in the same regimen, and if lack of response is seen to one entry inhibitor another can be tried. When selecting an entry inhibitor, physicians should account for patient preferences and needs as well as agent-specific clinical characteristics. Absence of documented multidrug resistance should not exclude an individual from treatment with an entry inhibitor; entry inhibitors are a valuable treatment option for all individuals who are treatment limited or treatment exhausted. We should advocate for additional clinical trials that help define the role of entry inhibitors in people with exhausted/limited ART options other than drug resistance., (© 2022 The Authors. HIV Medicine published by John Wiley & Sons Ltd on behalf of British HIV Association.)

Background: The durability of immune responses to COVID-19 vaccines among older people living with HIV (PWH) is clinically important., Methods: We aimed to assess vaccine-induced humoral immunity and durability in older PWH (≥ 55 years, n = 26) over 6 months (post-initial BNT162b2 series). A secondary and exploratory objective was to assess T-cell response and BNT162b2 booster reactogenicity, respectively. Our Visit 1 (3 weeks post-initial BNT162b2 dose) SARS-CoV-2 humoral immunity results are previously reported; these subjects were recruited for Visit 2 [2 weeks (+ 1 week window) post-second vaccination] and Visit 3 [6 months (± 2 week window) post-initial vaccination] in a single-center longitudinal observational study. Twelve participants had paired Visit 2/3 SARS-CoV-2 Anti-Spike IgG data. At Visit 3, SARS-CoV-2 Anti-Spike IgG testing occurred, and 5 subjects underwent T-cell immune response evaluation. Thereafter, subjects were offered BNT162b2 booster (concurrent day outside our study) per US FDA/CDC guidance; reactogenicity was assessed. The primary study outcome was presence of detectable Visit 3 SARS-CoV-2 Anti-Spike-1-RBD IgG levels. Secondary and exploratory outcomes were T-cell immune response and BNT162b2 booster reactogenicity, respectively. Wilcoxon signed-rank tests analyzed median SARS-CoV-2 Anti-Spike IgG 6-month trends., Results: At Visit 3, 26 subjects underwent primary analysis with demographics noted: Median age 61 years; male n = 16 (62%), female n = 10 (38%); Black n = 13 (50%), White n = 13 (50%). Most subjects (n = 20, 77%) had suppressed HIV viremia on antiretroviral therapy, majority (n = 24, 92%) with CD4 > 200 cells/µL. At Visit 3, 26/26 (100%) had detectable Anti-Spike-1-RBD (≥ 0.8 U/mL). Among 12 subjects presenting to Visit 2/3, median SARS-CoV-2 Anti-Spike 1-RBD was 2087 U/mL at Visit 2, falling to 581.5 U/mL at Visit 3 (p = 0.0923), with a median 3.305-fold decrease over 6 months. Among subjects (n = 5) with 6-month T-cell responses measured, all had detectable cytokine-secreting anti-spike CD4 responses; 3 had detectable CD4 + Activation induced marker (AIM) + cells. Two had detectable cytokine-secreting CD8 responses, but all had positive CD8 + AIM + cells., Conclusions: Among older PWH, SARS-CoV-2 Anti-Spike IgG and virus-specific T-cell responses are present 6 months post-primary BNT162b2 vaccination, and although waning, suggest retention of some degree of long-term protective immunity., (© 2022. The Author(s).)

Microbes play important roles in cancer from direct carcinogenic effects to their use in treatment. Cancers caused by microorganisms account for approximately 15% of cancers, primarily in low- and middle-income countries. Unique features of infectious carcinogens include their transmissibility, mutability, and specific immune interactions, which provide challenges and opportunities for cancer prevention and treatment. For these agents, infection control through exposure reduction, antivirals, antibiotics, and vaccines is cancer control. In addition, developing evidence suggests that microorganisms including the human microbiome can indirectly modulate cancer formation and influence the effectiveness and toxicity of cancer treatments. Finally, microorganisms themselves can be used to prevent or treat cancer. The convergence of these factors signals the emergence of a new field, cancer microbiology. Recognition of cancer microbiology will spur research, stimulate cross-disciplinary training, inform drug development, and improve public health., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: People living with HIV (PLWH) have increased risk of developing cancers after controlling traditional risk factors and viral suppression. This study explores whether T cells can serve as a marker of risk for cancer among HIV-infected virally suppressed patients., Methods: A nested case control study design was pursued with 17 cancer cases and 73 controls (PLWH without cancer)ouidentified among the US Military HIV Natural History Study cohort, and were matched for CD4 + count, duration of HIV infection, and viral suppression. Cells were obtained from PLWH on an average of 12 months prior to clinical cancer diagnosis. Expression of inhibitory receptors (PD-1, CD160, CD244, Lag-3, and TIGIT), and transcription factors (T-bet, Eomesodermin, TCF-1, and (TOX) was measured on CD8 +T cells from that early time point., Results: We found that cases have increased expression of PD-1 +CD160+CD244+ ('triple positive') on total and effector CD8 + compared with controls (p=0.02). Furthermore, CD8 +T cells that were both PD-1 +CD160+CD244+ and T-bet dim Eomes hi were significantly elevated in cases at time point before cancer detection, compared with controls without cancer (p=0.008). This was driven by the finding that transcriptional factor profile of cells was altered in cancers compared with controls. Triple-positive cells were noted to retain the ability for cytotoxicity and cytokine secretion mediated by expression of CD160 and PD-1, respectively. However, triple-positive cells demonstrated high expression of TOX-1, a transcription factor associated with T cell exhaustion., Conclusion: In conclusion, we have found a subset of dysfunctional CD8 +T cells, PD-1 +CD160+CD244+T-bet dim Eomes hi , that is elevated 12 months before cancer diagnosis, suggesting that peripheral T cell alterations may serve as a biomarker of increased cancer risk among PLWH., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

A common metabolic alteration in the tumor microenvironment (TME) is lipid accumulation, a feature associated with immune dysfunction. Here, we examined how CD8 + tumor infiltrating lymphocytes (TILs) respond to lipids within the TME. We found elevated concentrations of several classes of lipids in the TME and accumulation of these in CD8 + TILs. Lipid accumulation was associated with increased expression of CD36, a scavenger receptor for oxidized lipids, on CD8 + TILs, which also correlated with progressive T cell dysfunction. Cd36 -/- T cells retained effector functions in the TME, as compared to WT counterparts. Mechanistically, CD36 promoted uptake of oxidized low-density lipoproteins (OxLDL) into T cells, and this induced lipid peroxidation and downstream activation of p38 kinase. Inhibition of p38 restored effector T cell functions in vitro, and resolution of lipid peroxidation by overexpression of glutathione peroxidase 4 restored functionalities in CD8 + TILs in vivo. Thus, an oxidized lipid-CD36 axis promotes intratumoral CD8 + T cell dysfunction and serves as a therapeutic avenue for immunotherapies., Competing Interests: Declaration of interests G.C. receives research funding from Bayer AG and Boehringer Ingelheim, but the funding is not relevant to the current study. J.L.W. and X.S. are named inventors on patent applications or patents related to the use of oxidation-specific antibodies held by UCSD. R.Z. is an inventor on patent applications related to work on GITR, PD-1, and CTLA-4. R.Z. is a consultant for Leap Therapeutics and iTEOS. T.M. is a cofounder and holds equity in IMVAQ Therapeutics. T.M. is a consultant for Immunos Therapeutics, Pfizer, and Immunogenesis. T.M. has research support from Bristol-Myers Squibb; Surface Oncology; Kyn Therapeutics; Infinity Pharmaceuticals, Inc.; Peregrine Pharmaceuticals, Inc.; Adaptive Biotechnologies; Leap Therapeutics, Inc.; and Aprea. T.M. has patents on applications related to work on oncolytic viral therapy, alpha virus-based vaccines, neoantigen modeling, CD40, GITR, OX40, PD-1, and CTLA-4. J.D.W. is a consultant for Adaptive Biotech, Amgen, Apricity, Ascentage Pharma, Astellas, AstraZeneca, Bayer, Beigene, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Chugai, Elucida, Eli Lilly, F Star, Georgiamune, Imvaq, Kyowa Hakko Kirin, Linneaus, Merck Pharmaceuticals, Neon Therapeutics, Polynoma, Psioxus, Recepta, Takara Bio, Trieza, Truvax, Sellas Life Sciences, Serametrix, Surface Oncology, Syndax, Syntalogic, and Werewolf Therapeutics. J.D.W. reports grants from Bristol Myers Squibb and Sephora. J.D.W. has equity in Tizona Pharmaceuticals, Adaptive Biotechnologies, Imvaq, Beigene, Linneaus, Apricity, Arsenal IO, and Georgiamune. J.D.W. is an inventor on patent applications related to work on DNA vaccines in companion animals with cancer, assays for suppressive myeloid cells in blood, oncolytic viral therapy, alphavirus-based vaccines, neo-antigen modeling, CD40, GITR, OX40, PD-1, and CTLA-4., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: This study aimed to compare demographics, disease characteristics, and outcomes of patients with HIV-infection with non-small-cell lung cancer (NSCLC) with the general NSCLC population., Patients and Methods: A retrospective cohort study was used to compare the HIV-infected and -uninfected groups. Medical records of all patients who were HIV-positive diagnosed with NSCLC between 2000 and 2016 at Yale New Haven Hospital (New Haven, CT) were reviewed and compared with the general Yale NSCLC population regarding demographics, NSCLC characteristics, treatment, and survival. Log-rank tests and Kaplan-Meier curves were used to analyze survival differences. Unadjusted and adjusted Cox proportional hazard models were used to assess predictors of survival., Results: Thirty-five patients with HIV-NSCLC and 5187 general patients with NSCLC were identified. The median age at cancer diagnosis was 54 years (interquartile range [IQR], 49-59 years) for patients with HIV-NSCLC versus 68 years (IQR, 61-76 years) for patients with NSCLC (P < .001). Both groups had high rates of tobacco use. At the time of NSCLC diagnosis, 80% of patients with HIV-NSCLC were on antiretroviral therapy, 60% had an HIV-1 RNA < 400 copies/mL, and their median CD4 was 407 cells/μL (IQR, 218-592 cells/μL). Histology, cancer stage, and first-line cancer treatment regimens were not significantly different between groups. The overall median survival was 12.4 months (95% confidence interval [CI], 7.2-20.4 months) for patients with HIV-NSCLC versus 22.8 months (95% CI, 21.2-24.1 months) for general patients with NSCLC. Patients with HIV-NSCLC had decreased survival at 2 years (P = .028) and 3 years (P = .014) compared with general patients with NSCLC. HIV status was an independent risk factor for poorer outcomes when controlling for other factors (hazard ratio, 1.8; 95% CI, 1.24-2.62)., Conclusion: Despite similar histology, stage, and treatment between groups, patients with HIV had worse outcomes for NSCLC., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Hepatocellular carcinoma (HCC) can have viral or non-viral causes 1-5 . Non-alcoholic steatohepatitis (NASH) is an important driver of HCC. Immunotherapy has been approved for treating HCC, but biomarker-based stratification of patients for optimal response to therapy is an unmet need 6,7 . Here we report the progressive accumulation of exhausted, unconventionally activated CD8 + PD1 + T cells in NASH-affected livers. In preclinical models of NASH-induced HCC, therapeutic immunotherapy targeted at programmed death-1 (PD1) expanded activated CD8 + PD1 + T cells within tumours but did not lead to tumour regression, which indicates that tumour immune surveillance was impaired. When given prophylactically, anti-PD1 treatment led to an increase in the incidence of NASH-HCC and in the number and size of tumour nodules, which correlated with increased hepatic CD8 + PD1 + CXCR6 + , TOX + , and TNF + T cells. The increase in HCC triggered by anti-PD1 treatment was prevented by depletion of CD8 + T cells or TNF neutralization, suggesting that CD8 + T cells help to induce NASH-HCC, rather than invigorating or executing immune surveillance. We found similar phenotypic and functional profiles in hepatic CD8 + PD1 + T cells from humans with NAFLD or NASH. A meta-analysis of three randomized phase III clinical trials that tested inhibitors of PDL1 (programmed death-ligand 1) or PD1 in more than 1,600 patients with advanced HCC revealed that immune therapy did not improve survival in patients with non-viral HCC. In two additional cohorts, patients with NASH-driven HCC who received anti-PD1 or anti-PDL1 treatment showed reduced overall survival compared to patients with other aetiologies. Collectively, these data show that non-viral HCC, and particularly NASH-HCC, might be less responsive to immunotherapy, probably owing to NASH-related aberrant T cell activation causing tissue damage that leads to impaired immune surveillance. Our data provide a rationale for stratification of patients with HCC according to underlying aetiology in studies of immunotherapy as a primary or adjuvant treatment.

Background: Neurocognitive dysfunction remains prevalent among people living with HIV (PLWH), even after viral suppression on combination antiretroviral therapy (cART). We investigated associations between neuropsychological performance (NP) and patterns of circulating exosomal microRNA (exo-miRNA) expression in PLWH on cART., Setting: A cross-sectional examination of plasma exo-miRNA among PLWH on cART with systemic viral suppression and volunteers without HIV infection., Methods: Thirty-one PLWH who started cART during early infection (n = 19) or chronic infection (n = 12) participated in phlebotomy and an 11-test neuropsychological battery after >1 year on treatment. NP higher- or lower-performing participants were categorized based on normalized neuropsychological scores. Total RNA was extracted from purified exosomes of 31 PLWH and 5 volunteers without HIV and subject to small RNA sequencing. Differential expression of exo-miRNAs was examined and biological functions were predicted., Results: Eleven exo-miRNAs were up-regulated in NP lower-performing (n = 18) relative to higher-performing PLWH (n = 13). A high proportion of the differentiating exo-miRNA target the axon guidance KEGG pathway and neurotrophin tyrosine receptor kinase signaling Gene Ontology pathway. Differential expression analysis of exo-miRNAs between NP lower- (n = 7) and higher-performing (n = 12) PLWH within the early infection group alone confirmed largely consistent findings., Conclusions: Plasma exo-miRNA content differed between NP higher- and lower-performing PLWH. Several differentially expressed exo-miRNAs were predicted to be involved in inflammation and neurodegeneration pathways. Exo-miRNA in plasma may indicate cross-talk between the circulation and central nervous system and thus may be clinically relevant for neurocognitive dysfunction in PLWH.

Importance: Anti-PD-1 (anti-programmed cell death 1) and anti-PD-L1 (anti-programmed cell death ligand 1) regimens are preferred therapies for many cancers, including cancers associated with HIV. However, patients with HIV were excluded from most registered trials., Objective: The primary objective was to evaluate the safety of pembrolizumab in people with HIV and advanced cancer; the secondary objective was to evaluate tumor responses., Design, Setting, and Participants: Open-label, nonrandomized, phase 1 multicenter study conducted at 7 Cancer Immunotherapy Trials Network sites. Patients with HIV and advanced cancer as well as a CD4 count greater than or equal to 100 cells/μL, antiretroviral therapy (ART) for 4 or more weeks, and an HIV viral load of less than 200 copies/mL were eligible. Exclusion criteria included uncontrolled hepatitis B or C infection, active immunosuppressive therapy, or a history of autoimmune disease requiring systemic therapy., Interventions: Pembrolizumab, 200 mg, administered intravenously every 3 weeks for up to 35 doses in 3 CD4 count-defined cohorts. Participants continued ART., Main Outcomes and Measures: Safety and tolerability were assessed using current NCI Common Terminology Criteria for Adverse Events. Immune-related adverse events grade 2 or higher were considered immune-related events of clinical interest (irECI). Tumor responses were evaluated using standard tumor-specific criteria., Results: Thirty participants (28 men and 2 women; median [range] age, 57 [39-77] years) were enrolled from April 2016 through March 2018; 6 had Kaposi sarcoma (KS), 5 had non-Hodgkin lymphoma (NHL), and 19 had non-AIDS-defining cancers. Safety was observed over 183 cycles of treatment with pembrolizumab. Most treatment-emergent adverse events at least possibly attributed to pembrolizumab were grade 1 or 2 (n = 22), and 20% (n = 6) were grade 3. The irECI included hypothyroidism (6 participants), pneumonitis (3 participants), rash (2 participants), an elevated aminotransferase/alanine aminotransferase level (1 participant), and a musculoskeletal event (1 participant). One participant with pretreatment KS herpesvirus (KSHV) viremia developed a polyclonal KSHV-associated B-cell lymphoproliferation and died. HIV was controlled in all participants. Increases in CD4 count were not statistically significant (median increase, 19 cells/μL; P = .18). Best tumor responses included complete response (lung, 1 patient), partial response (NHL, 2 patients), stable disease for 24 weeks or more (KS, 2 patients), stable disease for less than 24 weeks (15 patients), and progressive disease (8 patients); 2 patients were not evaluable., Conclusions and Relevance: Pembrolizumab has acceptable safety in patients with cancer, HIV treated with ART, and a CD4+ T-cell count of greater than 100 cells/μL but may be associated with KSHV-associated B-cell lymphoproliferation. Clinical benefit was noted in lung cancer, NHL, and KS. Anti-PD-1 therapy is appropriate for US Food and Drug Administration-approved indications and clinical trials in this population., Trial Registration: ClinicalTrials.gov identifier: NCT02595866.

Background: Ibalizumab, a humanized IgG4 monoclonal antibody, blocks the entry of human immunodeficiency virus type 1 (HIV-1) by noncompetitive binding to CD4., Methods: In this single-group, open-label, phase 3 study, we enrolled 40 adults with multidrug-resistant (MDR) HIV-1 infection in whom multiple antiretroviral therapies had failed. All the patients had a viral load of more than 1000 copies of HIV-1 RNA per milliliter. After a 7-day control period in which patients continued to receive their current therapy, a loading dose of 2000 mg of ibalizumab was infused; the viral load was quantified 7 days later. Through week 25 of the study, patients received 800 mg of ibalizumab every 14 days, combined with an individually optimized background regimen including at least one fully active agent. The primary end point was the proportion of patients with a decrease in viral load of at least 0.5 log 10 copies per milliliter from baseline (day 7) to day 14., Results: A total of 31 patients completed the study. The mean baseline viral load was 4.5 log 10 copies per milliliter, and the mean CD4 count was 150 per microliter. Of the 40 patients in the intention-to-treat population, 33 (83%) had a decrease in viral load of at least 0.5 log 10 copies per milliliter from baseline (P<0.001 for the comparison with the control period). The mean viral-load decrease was 1.1 log 10 copies per milliliter. During the control period, 1 patient, who received the optimized background regimen prematurely, had a decrease in viral load of 0.5 log 10 copies per milliliter. At week 25, patients who had received ibalizumab plus an optimized background regimen had a mean decrease of 1.6 log 10 copies per milliliter from baseline; 43% of the patients had a viral load of less than 50 copies per milliliter, and 50% had a viral load of less than 200 copies per milliliter. Among 10 patients who had virologic failure or rebound, in vitro testing identified 9 who had a lower degree of susceptibility to ibalizumab than at baseline. The most common adverse event was diarrhea (in 20% of patients). Four patients died from causes related to underlying illnesses; 1 had a serious adverse event (the immune reconstitution inflammatory syndrome) that was deemed to be related to ibalizumab therapy., Conclusions: In patients with MDR HIV-1 infection who had advanced disease and limited treatment options, ibalizumab had significant antiviral activity during a 25-week study. Evidence of the emergence of diminished ibalizumab susceptibility was observed in vitro in patients who had virologic failure. (Funded by the Orphan Products Clinical Trials Grants Program of the Food and Drug Administration and TaiMed Biologics; TMB-301 ClinicalTrials.gov number, NCT02475629 .).

Introduction: Despite major progress in controlling HIV disease through antiretroviral therapy, changes in immune phenotype and function persist in individuals with chronic HIV, raising questions about accelerated aging of the immune system., Methods: We conducted a cross-sectional study (2005-2007) of HIV-infected (n = 111) and uninfected (n = 114) men from the Veterans Aging Cohort Study. All HIV-infected subjects were on antiretroviral therapy with VL <400 copies/mL for at least 3 years. T-cell markers were examined using flow cytometry. We evaluated the impact of HIV serostatus and age on T-cell phenotypes (expressed as percentages of the total CD4 and CD8 T-cell population) using multivariate linear regression, adjusted for smoking, alcohol, and race/ethnicity. We tested for interactions between HIV and age by including interaction terms., Results: Among both HIV-infected and uninfected subjects, increasing age was associated with a decreased proportion of naive CD4 T cells (P = 0.014) and CD8 T cells (P < 0.0001). Both HIV infection and increasing age were associated with higher proportions of effector memory CD4 T cells (P < 0.0001 for HIV; P = 0.04 for age) and CD8 T cells (P = 0.0001 for HIV; P = 0.0004 for age). HIV infection, but not age, was associated with a higher proportion of activated CD8 T cells (P < 0.0001). For all T-cell subsets tested, there were no significant interactions between HIV infection and age., Conclusions: Age and HIV status independently altered the immune system, but we found no conclusive evidence that HIV infection and advancing age synergistically result in accelerated changes in age-associated T-cell markers among virally suppressed individuals.

Background: In 2002, a previously healthy 69-year-old man travelled to France from the United States and presented to our hospital with a febrile illness that subsequently was determined to be babesiosis. The blood isolated from this patient served as a source for propagation of the Babesia microti R1 strain with subsequent sequencing and annotation of the parasite genome., Methods: Upon admission, we obtained a medical history, performed a physical examination, and examined his blood for the presence of a blood borne pathogen by microscopy, PCR and indirect immunofluorescence antibody testing. Once the diagnosis of babesiosis was made, we reviewed the literature to assess the distribution of B. microti-associated babesiosis cases in immunocompetent patients from outside the USA., Results: The patient recalled a tick bite during the previous month on Cape Cod, Massachusetts. The diagnosis was confirmed by identification of Babesia-infected red blood cells on blood smears, amplification of B. microti DNA in blood by PCR and the presence of B. microti antibody in the serum. This strain was the first isolate of B. microti to be fully sequenced and its annotated genome serves as a reference for molecular and cell biology studies aimed at understanding B. microti pathophysiology and developing diagnostic tests and therapies. A review of babesiosis cases demonstrates a worldwide distribution of B. microti and identifies potential emerging endemic areas where travelers may be at risk of contracting B. microti infection., Conclusion: This case provides clinical information about the patient infected with the R1 isolate and a review of travel risk, diagnosis and treatment of babesiosis in endemic and non-endemic areas., (© International Society of Travel Medicine, 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com)

Background: Lung cancer is a major cause of death in HIV-infected (HIV+) persons. In this study, we compared the prevalence of tumour EGFR and KRAS mutations in a cohort of lung adenocarcinoma patients by HIV status., Methods: We collected data from 55 HIV+ patients with lung adenocarcinoma matched to 136 uninfected comparators. We compared the prevalence of EGFR and KRAS mutations by HIV status. We then compared survival by HIV status and by cancer mutation status among HIV+ subjects., Results: Presence of KRAS and EGFR genetic alterations did not vary by HIV status (all P>0.1). There was no difference in overall survival by HIV status or by mutation status among HIV+ subjects., Conclusions: We found no major differences in the prevalence of EGFR or KRAS lung adenocarcinoma mutations by HIV status, suggesting that mutational testing should be conducted similarly regardless of the HIV status.

Objectives: Opioids have immunosuppressive properties, yet opioid effects on T cell abnormalities consistent with the immune risk phenotype among HIV-infected individuals are understudied., Methods: To assess associations between illicit opioid use and T cell characteristics (CD4/CD8 ratio, memory profiles based on CD45RO and CD28 expression, and senescence based on CD57 expression), we conducted an exploratory cross-sectional analysis of Russia ARCH, a cohort of antiretroviral therapy (ART)-naïve HIV-infected individuals recruited 11/2012 to 10/2014 in St. Petersburg, Russia. The main independent variable was past 30 day illicit opioid use (yes vs. no). Secondary analyses evaluated none (0 days), intermittent (1 to 7 days), and persistent (8 to 30 days) opioid use. Outcomes were determined with flow cytometry. Analyses were conducted using linear regression models., Results: Among 186 participants, 38% reported any illicit opioid use (18% intermittent and 20% persistent). Any illicit opioid use was not significantly associated with T cell characteristics. Intermittent opioid use appeared to be associated with decreased memory CD8+ T cells proportion (CD45RO+CD45RA- CD8+ T cells: adjusted mean difference [AMD] [95% CI] = -6.15 [-11.50, -0.79], p = 0.02) and borderline significant increased senescent T cells (%CD57+ of total CD28-CD8+ T cells (AMD [95% CI] = 7.70 [-0.06, 15.46], p = 0.05)., Conclusions: Among ART-naïve HIV-infected Russians, any illicit opioid use was not significantly associated with T cell abnormalities although intermittent illicit opioid use may be associated with CD8 T cell abnormalities. Longitudinal studies are warranted to confirm these findings given increased risk of infections and comorbidities seen among HIV-infected individuals with illicit opioid use.

Cytomegalovirus (CMV) infection is a significant complication after kidney transplantation. We examined the ability of RG7667, a combination of two monoclonal antibodies, to prevent CMV infection in high-risk kidney transplant recipients in a randomized, double-blind, placebo-controlled trial. CMV-seronegative recipients of a kidney transplant from a CMV-seropositive donor (D+R-) were randomized to receive RG7667 (n = 60) or placebo (n = 60) at the time of transplant and 1, 4, and 8 weeks posttransplant. Patients were monitored for CMV viremia every 1 to 2 weeks posttransplant for 24 weeks. Patients who had seroconverted (D+R+) or withdrawn before dosing were excluded from the analysis (n = 4). CMV viremia occurred in 27 of 59 (45.8%) patients receiving RG7667 and 35 of 57 (61.4%) patients receiving placebo (stratum-adjusted difference, 15.3%; P = 0.100) within 12 weeks posttransplant and in 30 of 59 (50.8%) patients receiving RG7667 and 40 of 57 (70.2%) patients receiving placebo (stratum-adjusted difference, 19.3%; P = 0.040) within 24 weeks posttransplant. Median time to CMV viremia was 139 days in patients receiving RG7667 compared to 46 days in patients receiving placebo (hazard ratio, 0.53; P = 0.009). CMV disease was less common in the RG7667 than placebo group (3.4% versus 15.8%; P = 0.030). Adverse events were generally balanced between treatment groups. In high-risk kidney transplant recipients, RG7667 was well tolerated, numerically reduced the incidence of CMV infection within 12 and 24 weeks posttransplant, delayed time to CMV viremia, and was associated with less CMV disease than the placebo. (This study has been registered at ClinicalTrials.gov under registration no. NCT01753167.)., (Copyright © 2017 American Society for Microbiology.)

Epigenetic control of human immunodeficiency virus-1 (HIV-1) genes is critical for viral integration and latency. However, epigenetic changes in the HIV-1-infected host genome have not been well characterized. Here, we report the first large-scale epigenome-wide association study of DNA methylation for HIV-1 infection. We recruited HIV-infected (n = 261) and uninfected (n = 117) patients from the Veteran Aging Cohort Study (VACS) and all samples were profiled for 485,521 CpG sites in DNA extracted from the blood. After adjusting for cell type and clinical confounders, we identified 20 epigenome-wide significant CpGs for HIV-1 infection. Importantly, 2 CpGs in the promoter of the NLR family, CARD domain containing gene 5 (NLRC5), a key regulator of major histocompatibility complex class I gene expression, showed significantly lower methylation in HIV-infected subjects than in uninfected subjects (cg07839457: t = -6.03, P nominal = 4.96 × 10 -9 ; cg16411857: t = -7.63, P nominal = 3.07 × 10 -13 ). Hypomethylation of these 2 CpGs was replicated in an independent sample (GSE67705: cg07839457: t = -4.44, P nominal = 1.61 × 10 -5 ; cg16411857: t = -5.90; P = 1.99 × 10 -8 ). Methylation of these 2 CpGs in NLRC5 was negatively correlated with viral load in the 2 HIV-infected samples (cg07839457: P = 1.8 × 10 -4 ; cg16411857: P = 0.03 in the VACS; and cg07839457: P = 0.04; cg164111857: P = 0.01 in GSE53840). Our findings demonstrate that differential DNA methylation is associated with HIV infection and suggest the involvement of a novel host gene, NLRC5, in HIV pathogenesis.

Cytomegalovirus can cause debilitating and life-threatening disease in newborns infected in utero and immunocompromised individuals, including transplant recipients. RG7667 is a unique combination of two monoclonal antibodies that binds glycoprotein complexes on the surface of cytomegalovirus and inhibits its entry into host cells. A phase 1 first-in-human, randomized, double-blind, placebo-controlled, dose-escalation study of RG7667 given intravenously was conducted in 181 healthy adults. The study involved a single ascending dose stage (1, 3, 5, and 10 mg/kg each antibody; n = 21), a multiple ascending dose stage (5 and 10 mg/kg each antibody monthly for 3 doses; n = 10), and a multiple dose expansion stage (10 mg/kg each antibody monthly for 3 doses; n = 150). Subjects were followed for 85 to 141 days to evaluate safety, tolerability, pharmacokinetics, and immunogenicity. Most adverse events were mild, and the incidence of adverse events was similar among the RG7667 and placebo groups. RG7667 had dose-proportional pharmacokinetics in all three dosing stages, a mean terminal half-life of 20 to 30 days, and an overall pharmacokinetic profile consistent with that of a human monoclonal antibody that lacks endogenous host targets. The proportion of subjects developing an antitherapeutic antibody response was not higher in the RG7667 group than in the placebo group. In summary, single and multiple doses of RG7667 were found to be safe and well-tolerated in healthy adults and had a favorable pharmacokinetic and immunogenicity profile. This study supports further development of RG7667 as a therapy for the prevention and treatment of cytomegalovirus infection in susceptible populations. (This study has been registered at ClinicalTrials.gov under registration no. NCT01496755.)., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

The ability to reconstitute a normal immune system with antiretroviral therapy in the setting of HIV infection remains uncertain. This study aimed to characterize quantitative and qualitative aspects of various T cell subpopulations that do not improve despite effective ART. CD4∶CD8 ratio was evaluated in HIV-infected subjects with viral loads >10,000 copies/µl ("non-controllers", n = 42), those with undetectable viral loads on ART ("ART-suppressed", n = 53), and HIV-uninfected subjects (n = 22). In addition, T cell phenotype and function were examined in 25 non-controllers, 18 ART-suppressed, and 7 HIV-uninfected subjects. CD4∶CD8 ratio in non-controllers, ART-suppressed, and HIV-uninfected subjects was 0.25, 0.48, and 1.95 respectively (P<0.0001 for all comparisons). The increased ratio in ART-suppressed compared to non-controllers was driven by an increase of CD4+ T cells, with no change in the expanded CD8+ T cell population. Expansion of differentiated (CD28-CD27-CD45RA+/-CCR7-) T cell subpopulations persisted despite ART and minimal changes were noted in naïve T cell frequencies over time. Increased number of CD8+CD28- T cells and increased CD8+ CMV-specific T cell responses were associated with a decreased CD4∶CD8 ratio. Measures of T cell function demonstrated persistence of high frequencies of CD8+ T cells producing IFN-γ. Lastly, though all CD8+ subpopulations demonstrated significantly lower Ki67 expression in ART-suppressed subjects, CD4+ T cell subpopulations did not consistently show this decrease, thus demonstrating different proliferative responses in the setting of T cell depletion. In summary, this study demonstrated that CD4∶CD8 ratios remained significantly decreased and naïve T cell numbers were slow to increase despite long-term viral suppression on ART. In addition, there is a evidence of differential regulation of the CD4+ and CD8+ T cell subpopulations, suggesting independent homeostatic regulation of the two compartments.

Introduction: Pateclizumab (MLTA3698A) is a humanized mAb against lymphotoxin α (LTα), a transiently expressed cytokine on activated B and T cells (Th1, Th17), which are implicated in rheumatoid arthritis (RA) pathogenesis. This study was conducted to assess the safety, tolerability, < NOTE: For clarity and per AMA/S-W Style, please restore the use of Oxford/serial commas (ie: David likes vanilla, strawberry, and chocolate ice cream) throughout. and biologic activity of single and multiple doses of intravenous (IV) or subcutaneous (SC) pateclizumab in RA patients., Methods: The single ascending dose (SAD) phase in patients with stable RA consisted of six cohorts (4:1 active:placebo at 0.3 mg/kg IV, 1.0 mg/kg IV, 1.0 mg/kg SC, 3.0 mg/kg IV, 3.0 mg/kg SC, and 5.0 mg/kg IV; n = 5/cohort). In the multiple ascending dose (MAD) phase, patients with prespecified RA disease activity received three doses of pateclizumab or placebo (4:1) every 2 weeks (1.0 mg/kg SC, n = 10; 3.0 mg/kg SC, n = 20; or 5.0 mg/kg IV, n = 5). Safety and tolerability were assessed throughout, and clinical activity was determined after three doses (Week 6)., Results: We observed no serious adverse events (AEs) or dose-limiting toxicities, and the majority of AEs were mild to moderate. The pharmacokinetic profiles were linear, and clearance was independent of dose. Reductions in levels of serum CXCL13 were observed, supporting the biologic activity of pateclizumab on the LTα pathway. Patients receiving pateclizumab in the 3.0 mg/kg MAD group (3.0 mg/kg SC) demonstrated ACR20, ACR50, and ACR70 response rates at week 6 of 75%, 56% and 25%, respectively, compared with 57%, 29%, and 0% in the placebo group. The median Disease Activity Score in 28 joints, C-reactive protein, reduction was 28% for pateclizumab, versus 8.4% for placebo., Conclusions: Pateclizumabwas generally well-tolerated in RA patients. Preliminary evidence of clinical activity was observed in active RA patients at the dose level targeted for clinical effect.

HIV infection can result in depletion of total CD4(+) T cells and naive CD8(+) T cells, and in the generation of dysfunctional effector CD8(+) T cells. In this study, we show that naive CD8(+) T cells in subjects with progressive HIV disease express low levels of CD8α and CD8β chains. Such naive CD8(low) T cells display broad signaling defects across the T-cell receptor complex, and their appearance correlates with generalized up-regulation of major histocompatibility complex class I (MHC-I) antigens on peripheral blood mononuclear cells (PBMCs). To explore a causal link between increased MHC-I up-regulation and the generation of naive CD8(low) T cells, we used the humanized SCID-hu Thy/Liv mouse model to show that HIV infection of the thymus and interferon α (IFNα) treatment alone result in MHC-I up-regulation and in the generation of dysfunctional CD3(high)CD8(+)CD4(-) single-positive 8 (SP8) thymocytes with low expression of CD8. We suggest that dysfunctional naive CD8(low) T cells are generated as a result of IFNα-mediated up-regulation of MHC-I on stromal cells in the thymus and antigen-presenting cells in the periphery, and that dysfunction in this naive compartment contributes to the immunodeficiency of HIV disease. This study is registered at www.clinicaltrials.gov as NCT00187512.

HIV-infected individuals maintaining undetectable viremia in the absence of therapy (HIV controllers) often maintain high HIV-specific T cell responses, which has spurred the development of vaccines eliciting HIV-specific T cell responses. However, controllers also often have abnormally high T cell activation levels, potentially contributing to T cell dysfunction, CD4+ T cell depletion, and non-AIDS morbidity. We hypothesized that a weak T regulatory cell (Treg) response might contribute to the control of viral replication in HIV controllers, but might also contribute to generalized immune activation, contributing to CD4+ T cell loss. To address these hypotheses, we measured frequencies of activated (CD38+ HLA-DR+), regulatory (CD4+CD25+CD127(dim)), HIV-specific, and CMV-specific T cells among HIV controllers and 3 control populations: HIV-infected individuals with treatment-mediated viral suppression (ART-suppressed), untreated HIV-infected "non-controllers" with high levels of viremia, and HIV-uninfected individuals. Despite abnormally high T cell activation levels, controllers had lower Treg frequencies than HIV-uninfected controls (P = 0.014). Supporting the propensity for an unusually low Treg response to viral infection in HIV controllers, we observed unusually high CMV-specific CD4+ T cell frequencies and a strong correlation between HIV-specific CD4+ T cell responses and generalized CD8+ T cell activation levels in HIV controllers (P ≤ 0.001). These data support a model in which low frequencies of Tregs in HIV controllers may contribute to an effective adaptive immune response, but may also contribute to generalized immune activation, potentially contributing to CD4 depletion.

A rare subset of human immunodeficiency virus (HIV)-infected individuals maintains undetectable HIV RNA levels without therapy ("elite controllers"). To clarify the role of T-cell responses in mediating virus control, we compared HLA class I polymorphisms and HIV-specific T-cell responses among a large cohort of elite controllers (HIV-RNA < 75 copies/ml), "viremic" controllers (low-level viremia without therapy), "noncontrollers" (high-level viremia), and "antiretroviral therapy suppressed" individuals (undetectable HIV-RNA levels on antiretroviral therapy). The proportion of CD4(+) and CD8(+) T cells that produce gamma interferon (IFN-gamma) and interleukin-2 (IL-2) in response to Gag and Pol peptides was highest in the elite and viremic controllers (P < 0.0001). Forty percent of the elite controllers were HLA-B*57 compared to twenty-three percent of viremic controllers and nine percent of noncontrollers (P < 0.001). Other HLA class I alleles more common in elite controllers included HLA-B*13, HLA-B*58, and HLA-B*81 (P < 0.05 for each). Within elite and viremic controller groups, those with protective class I alleles had higher frequencies of Gag-specific CD8(+) T cells than those without these alleles (P = 0.01). Noncontrollers, with or without protective alleles, had low-level CD8(+) responses. Thus, certain HLA class I alleles are enriched in HIV controllers and are associated with strong Gag-specific CD8(+)IFN-gamma(+)IL-2(+) T cells. However, the absence of evidence of T cell-mediated control in many controllers suggests the presence of alternative mechanisms for viral control in these individuals. Defining mechanisms for virus control in "non-T-cell controllers" might lead to insights into preventing HIV transmission or preventing virus replication.

Although cryopreservation of peripheral blood mononuclear cells (PBMC) is a commonly used technique, the degree to which it affects subsequent functional studies has not been well defined. Here we demonstrate that long-term cryopreservation has detrimental effects on T cell IFN-gamma responses in human immunodeficiency virus (HIV) infected individuals. Long-term cryopreservation caused marked decreases in CD4(+) T cell responses to whole proteins (HIV p55 and cytomegalovirus (CMV) lysate) and HIV peptides, and more limited decreases in CD8(+) T cell responses to whole proteins. These losses were more apparent in cells stored for greater than one year compared to less than six months. CD8(+) T cell responses to peptides and peptide pools were well preserved. Loss of both CD4(+) and CD8(+) T cell responses to CMV peptide pools were minimal in HIV-negative individuals. Addition of exogenous antigen presenting cells (APC) did not restore CD4(+) T cell responses to peptide stimulation and partially restored T cell IFN-gamma responses to p55 protein. Overnight resting of thawed cells did not restore T cell IFN-gamma responses to peptide or whole protein stimulation. A selective loss of phenotypically defined effector cells did not explain the decrement of responses, although cryopreservation did increase CD4(+) T cell apoptosis, possibly contributing to the loss of responses. These data suggest that the impact of cryopreservation should be carefully considered in future vaccine and pathogenesis studies. In HIV-infected individuals short-term cryopreservation may be acceptable for measuring CD4(+) and CD8(+) T cell responses. Long-term cryopreservation, however, may lead to the loss of CD4(+) T cell responses and mild skewing of T cell phenotypic marker expression.

Background: Diminished IL-2 production and lack of effector differentiation have been reported for HIV-specific T cells. In this study, we examined the prevalence of these phenomena using 8-color cytokine flow cytometry, and tested the hypothesis that these two findings were causally related. We analyzed cytokine profiles and memory/effector phenotypes of HIV-specific and CMV-specific T cells using short-term in vitro stimulation with HIV or CMV peptide pools. Nineteen HIV-positive subjects with progressive disease and twenty healthy, HIV-negative subjects were examined., Results: Among HIV-infected subjects, there were significantly fewer CD8+ IL-2+ T cells responding to HIV compared to CMV, with no significant difference in CD4+ IL-2+ T cells. The majority of CMV-specific T cells in both HIV-negative and HIV-positive subjects appeared to be terminally differentiated effector cells (CD8+ CD27- CD28- CD45RA+ or CD8+ CD27- CD28- CD45RA-). In HIV-positive subjects, the most common phenotype of HIV-specific T cells was intermediate in differentiation (CD8+ CD27+ CD28- CD45RA-). These differences were statistically significant, both as absolute cell frequencies and as percentages. There was a significant correlation between the absolute number of HIV-specific CD8+ IL-2+ T cells and HIV-specific CD8+ CD27- CD28- CD45RA+ terminal effector cells., Conclusion: IL-2 production from antigen-specific CD8+ T cells correlates with effector cell differentiation of those cells.

The human immunodeficiency virus (HIV)-mediated immune response may be beneficial or harmful, depending on the balance between expansion of HIV-specific T cells and the level of generalized immune activation. The current study utilizes multicolor cytokine flow cytometry to study HIV-specific T cells and T-cell activation in 179 chronically infected individuals at various stages of HIV disease, including those with low-level viremia in the absence of therapy ("controllers"), low-level drug-resistant viremia in the presence of therapy (partial controllers on antiretroviral therapy [PCAT]), and high-level viremia ("noncontrollers"). Compared to noncontrollers, controllers exhibited higher frequencies of HIV-specific interleukin-2-positive gamma interferon-positive (IL-2(+) IFN-gamma(+)) CD4(+) T cells. The presence of HIV-specific CD4(+) IL-2(+) T cells was associated with low levels of proliferating T cells within the less-differentiated T-cell subpopulations (defined by CD45RA, CCR7, CD27, and CD28). Despite prior history of progressive disease, PCAT patients exhibited many immunologic characteristics seen in controllers, including high frequencies of IL-2(+) IFN-gamma(+) CD4(+) T cells. Measures of immune activation were lower in all CD8(+) T-cell subsets in controllers and PCAT compared to noncontrollers. Thus, control of HIV replication is associated with high levels of HIV-specific IL-2(+) and IFN-gamma(+) CD4(+) T cells and low levels of T-cell activation. This immunologic state is one where the host responds to HIV by expanding but not exhausting HIV-specific T cells while maintaining a relatively quiescent immune system. Despite a history of advanced HIV disease, a subset of individuals with multidrug-resistant HIV exhibit an immunologic profile comparable to that of controllers, suggesting that functional immunity can be reconstituted with partially suppressive highly active antiretroviral therapy.