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This article provides a focused update to the clinical practice guideline on the treatment and management of patients with coronavirus disease 2019, developed by the Infectious Diseases Society of America. The guideline panel presents a recommendation on the use of the anti-severe acute respiratory syndrome coronavirus 2 neutralizing antibody pemivibart as pre-exposure prophylaxis. The recommendation is based on evidence derived from a systematic review and adheres to a standardized methodology for rating the certainty of evidence and strength of recommendation according to the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach. Information on pemivibart is included in the U.S. Food and Drug Administration Emergency Use Authorization for this agent., Competing Interests: Possible conflicts of interest. Evaluation of relationships as potential conflicts of interest is determined by a review process. The assessment of disclosed relationships for possible COIs is based on the relative weight of the financial relationship (ie, monetary amount) and the relevance of the relationship (ie, the degree to which an association might reasonably be interpreted by an independent observer as related to the topic or recommendation of consideration). The following panelists have research-related advisor/consultant roles for indicated companies: R.B. for Shionogi, Merck, and Gilead Sciences; K.W.C. for Pardes Biosciences (concluded); E.D. for Gilead Sciences; D.V.G. for Gilead Sciences and Merck; A.K. for Shionogi; S.S. for Pfizer; P.T. for Merck and Shionogi. Importantly, these companies have developed COVID-19 treatment (but not prophylaxis) agents. No disclosures reported for all other authors including the chair and vice chair. Additional information. More detailed information on the analysis and development of recommendations is available in the Supplementary material., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Development of a screening assay for the clinical use of broadly neutralizing antibodies (bnAbs) is a priority for HIV therapy and cure initiatives., Methods: We assessed the PhenoSense Monoclonal Antibody (mAb) Assay (Labcorp-Monogram Biosciences) which is CLIA-validated and has been used prospectively and retrospectively in multiple recent bnAb clinical trials., Results: When performed on pre-ART plasma and on-ART longitudinal PBMC samples sourced from a recent clinical trial, the PhenoSense mAb Assay produced robust reproducibility, concordance across sample types, and expected ranges in the susceptibility measures of bnAbs in clinical development. PhenoSense mAb applied retrospectively to baseline samples from three recent studies correlated with published laboratory-based study evaluations, but baseline bnAb susceptibility was not consistently predictive of durable virus suppression. Assessment of the feasibility of the assay in four recent clinical studies provides estimates of assay success rate and processing time., Conclusions: The PhenoSense mAb Assay provides reproducible bnAb susceptibility measurements across relevant sample types yet was not consistently predictive of virus suppression. Logistical and operational assay requirements can impact timely clinical trial conduct. These results inform bnAb studies in development., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Description: In March 2020, the White House Coronavirus Task Force determined that clinicians in the United States needed expert treatment guidelines to optimally manage patients with COVID-19, a potentially life-threatening disease caused by a new pathogen for which no specific treatments were known to be effective., Methods: The U.S. Department of Health and Human Services requested that the National Institutes of Health (NIH) take the lead in expeditiously convening a panel of experts to create "living" guidelines that would be widely accessible and capable of frequent updating as important new information became available., Recommendations: The purpose of this article is to expand on the experiences of the NIH COVID-19 Treatment Guidelines Panel (the Panel) over the past 4 years, summarize the Panel's final recommendations for COVID-19, highlight some challenges and unanswered questions about COVID-19 management, and inform future responses to public health emergencies. The Panel was formed in March 2020, and the first iteration of the guidelines was released in April 2020. Now that the public health emergency has ended, the NIH COVID-19 Treatment Guidelines have sunsetted. This role will now fall to professional societies and organizations, such as the American College of Physicians, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the World Health Organization, all of which have been active in this area., Competing Interests: Disclosures: Disclosure forms are available with the article online.

Type I IFNs play a pivotal role in immune response modulation, yet dysregulation is implicated in various disorders. Therefore, it is crucial to develop tools that facilitate the understanding of their mechanism of action and enable the development of more effective anti-IFN therapeutic strategies. In this study, we isolated, cloned, and characterized anti-IFN-α and anti-IFN-β Abs from PBMCs of individuals treated with IFN-α or IFN-β, harboring confirmed neutralizing Abs. Clones AH07856 and AH07857 were identified as neutralizing anti-IFN-α-specific with inhibition against IFN-α2a, -α2b, and -αK subtypes. Clones AH07859 and AH07866 were identified as neutralizing anti-IFN-β1a-specific signaling and able to block lipopolysaccharide or S100 calcium-binding protein A14-induced IFN-β signaling effects. Cloned Abs bind rhesus but not murine IFNs. The specificity of inhibition between IFN-α and IFN-β suggests potential for diverse research and clinical applications., (Copyright © 2024 by The American Association of Immunologists, Inc.)

Introduction: To assess the effectiveness of novel HIV curative strategies, "cure" trials require periods of closely monitored antiretroviral therapy (ART) analytical treatment interruptions (ATIs). We performed a systematic review and meta-analysis to identify the impact of ATI with or without novel therapeutics in cure-related studies on the time to viral re-suppression following ART restart., Methods: Medline, Embase and Web of Science databases were searched for human studies involving ATIs from 1 January 2015 till 22 April 2024. The primary outcome was time to first viral re-suppression (plasma HIV viral load [VL] <50 copies/ml) stratified by receipt of interventional drug with ATI (IA) or ATI-only groups. Random-effects proportional meta-analysis and multivariable Cox proportional hazards analysis were performed using R., Results: Of 1073 studies screened, 13 were included that met the inclusion criteria with VL data available after restarting ART (n = 213 participants). There was no difference between time to viral suppression in IA or ATI-only cohorts (p = 0.22). For 87% of participants, viral suppression within 12 weeks of ART restart was achieved, and all eventually had at least one VL <50 copies/ml during follow-up. After adjusting for covariables, while participants in the IA cohort were associated with less rapid suppression (adjusted hazard ratio [aHR] 0.61, 95% CI 0.40-0.94, p = 0.026), other factors include greater log VL at ART restart (aHR 0.56, 95% CI 0.46-0.68, p<0.001), duration since HIV diagnosis (aHR 0.93, 95% CI 0.89-0.96) and longer intervals between HIV VL monitoring (aHR 0.66, 95% CI 0.59-0.74, p<0.001). However, the use of integrase inhibitors was associated with more rapid viral suppression (aHR 1.74, 95% CI 1.16-2.59)., Discussion: When designing studies involving ATIs, information on time to viral re-suppression after restarting ART is important to share with participants, and should be regularly monitored and reported, to assess the impact and safety of specific trial interventions in ATI studies., Conclusions: The majority of participants achieved viral suppression after restarting ART in ATI studies. ART regimens containing integrase inhibitors and frequent VL monitoring should be offered for people restarting ART after ATI studies to ensure rapid re-suppression., (© 2024 The Author(s). Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of International AIDS Society.)

Background: During the COVID-19 pandemic, SARS-CoV-2 monoclonal antibodies for preexposure prophylaxis (SMA-PrEP) offered patients who were immunocompromised another option for protection. However, SMA-PrEP posed administrative, operational, and ethical challenges for health care facilities, resulting in few patients receiving them. Although the first SMA-PrEP medication, tixagevimab and cilgavimab, had its authorization revoked due to compromised in vitro efficacy, new SMA-PrEP medications are currently completing clinical trials. This article provides an operational framework for administrative organization, patient identification and prioritization, equitable medication allocation, medication ordering and administration, and patient tracking., Methods: A retrospective cohort study evaluating our hospital's SMA-PrEP administration strategy was performed. Multivariable logistic regression was used to examine factors associated with receipt of SMA-PrEP., Results: Despite the barriers in administering this medication and the scarcity of resources, our hospital was able to administer at least 1 dose of SMA-PrEP to 1359 of 5902 (23.0%) eligible patients. Even with the steps taken to promote equitable allocation, multivariable logistic regression demonstrated that there were still differences by race, ethnicity, and socioeconomic status. As compared with patients who identified as Black, patients who identified as White (odds ratio [OR], 1.85; 95% CI, 1.46-2.33), Asian (OR, 1.59; 95% CI, 1.03-2.46), and Hispanic (OR, 1.53; 95% CI, 1.02-2.44) were more likely to receive SMA-PrEP. When compared with patients with low socioeconomic status, patients with high socioeconomic status (OR, 1.37; 95% CI, 1.05-1.78) were more likely to be allocated SMA-PrEP., Conclusions: Despite efforts to mitigate health care disparities, differences by race/ethnicity and socioeconomic status still arose in patients receiving SMA-PrEP., Competing Interests: Potential conflicts of interest. D. A. J. has received personal fees for advisory board participation and/or consulting from Biogen, BMS, Cycle Pharma, Horizon, Merck/EMD Serono, Novartis, Roche/Genentech, TG Therapeutics, and Sanofi-Genzyme and grant support to the University of Pennsylvania from Biogen Idec, Roche/Genentech, Merck/EMD Serono, and Novartis. All other authors report no potential conflicts., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Doravirine and islatravir is an investigational, once-daily, single-tablet regimen with high antiviral potency, favourable safety and tolerability, and low propensity for resistance. We report week 48 results from a phase 3 trial evaluating switch from stable, oral antiretroviral therapy (ART) to the fixed combination of doravirine (100 mg) and islatravir (0·75 mg)., Methods: This phase 3, multicentre, randomised, active-controlled, open-label, non-inferiority trial was conducted at 77 research, community, and hospital-based clinics in 15 countries. Adults aged 18 years or older with fewer than 50 HIV-1 RNA copies per mL on any oral, two-drug or three-drug ART regimen for at least 3 months, and no history of previous virological failure on any past or current regimen were randomly assigned (1:1) by a computer-generated randomisation schedule to switch to doravirine (100 mg) and islatravir (0·75 mg) or to continue their baseline ART regimen. Block randomisation was based on a block size of four, and randomisation was stratified by baseline regimen (ie, protease inhibitor, integrase inhibitor, or other). Participants in the doravirine and islatravir group were instructed to take one tablet at approximately the same time each day, and participants in the baseline ART group continued to take the medication according to the locally approved label. HIV-1 RNA and safety evaluations were done at baseline and weeks 4, 12, 24, 36, and 48. CD4 cell counts were measured at baseline, week 24, and week 48. The primary endpoint was proportion of participants with greater than or equal to 50 HIV-1 RNA copies per mL at week 48 in the full analysis set (ie, all participants who received at least one dose of study drug) using the US Food and Drug Administration snapshot approach and prespecified non-inferiority margin of 4%. This study is registered with ClinicalTrials.gov (NCT04223778) and is completed., Findings: Between Feb 18 and Oct 2, 2020, 740 individuals were screened for eligibility, of whom 672 (90·8%) participants (249 [37·1%] women and 423 [62·9%] men; median CD4 count of 678 cells per μL [IQR 496-868]) were randomly assigned to doravirine (100 mg) and islatravir (0·75 mg; n=336) or to continue baseline ART (n=336). The last follow-up visit occurred on Sept 8, 2021. At week 48, zero of 336 participants in the doravirine and islatravir group versus five (1·5%) of 336 participants in the baseline ART group had greater than or equal to 50 HIV-1 RNA copies per mL (difference -1·5, 95% CI -3·4 to -0·3). The per-protocol analysis showed consistent results. Headache was the most common adverse event in both groups (35 [10·4%] of 336 participants in the doravirine and islatravir group, 16 [4·8%] of 336 in the baseline ART group), infection rates were similar (113 [33·6%] in both groups), and discontinuations due to adverse events were low (seven [2·1%] vs one [0·3%]). 66 (19·6%) of 336 participants had treatment-related adverse events in the doravirine and islatravir group compared with 30 (8·9%) of 336 in the baseline ART group. In the islatravir and doravirine group, CD4 cell counts (mean change -30·3 cells per μL) and total lymphocyte counts (mean change -0·26 × 10 9 /L) were decreased at 48 weeks., Interpretation: Switching to single-tablet doravirine (100 mg) and islatravir (0·75 mg) maintained viral suppression up to week 48 and was non-inferior to antiretroviral combinations used in clinical practice for adults with HIV-1; however, decreases in CD4 cell and total lymphocyte counts do not support further development of once-daily doravirine (100 mg) and islatravir (0·75 mg)., Funding: Merck Sharp & Dohme, a subsidiary of Merck & Co., Competing Interests: Declaration of interests J-MM reports a grant to his institution from Gilead; consulting fees from Gilead, ViiV, and Merck for advisory boards; payment from Merck for expert testimony; and participation on a data safety monitoring board for Aelix. GR reports honoraria for lectures from ViiV, GSK, and MSD and support from Gilead for attending meetings or travel. CO reports payment to the Desmond Tutu Health Foundation for the current study and honoraria and travel support from MSD for attendance and presentation at Expert Input Forum. AA declares no competing interests. AC reports unrestricted educational grants with MSD, Gilead Sciences, and ViiV Healthcare. SO reports research grants from MSD, ViiV Healthcare, and Gilead Sciences and honoraria for lectures from ViiV Healthcare and Gilead Sciences. FH reports research grants from AbbVie, VIR, Merck, and GSK; payment from AbbVie, Gilead, ViiV, and Merck for Speakers Bureau; and participation on a data safety monitoring board or advisory board for Viiv and Gilead. PK reports grants from Merck, Gilead, GSD/ViiV, and Theratechnologies; consulting fees from Merck, Gilead, Johnson & Johnson, GSK/ViiV, and Theratechnologies; participation on a data safety monitoring board or advisory board for Gilead, Merck, GSK/ViiV, Theratechnologies, and Johnson & Johnson; and stock or stock options with Merck, Gilead, Johnson & Johnson, Pfizer, and GSK. PT reports a grant from Merck to the University of Pennsylvania for the current study and consulting fees from Merck, Gilead, and ViiV. SW reports funding and provision of study materials from Merck for the current study; grants from Merck, ViiV Healthcare, Gilead Sciences, and Janssen; and consulting fees and honoraria for lectures from Merck and ViiV Healthcare. AG, SK, IG, KE, TAC, MCF, and JK are current or former employees of Merck Sharp & Dohme, a subsidiary of Merck & Co, and might own stock or stock options, or both, in the company., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Objective: The primary objective of the study was to assess the immunogenicity of an HIV-1 Gag conserved element DNA vaccine (p24CE DNA) in people with HIV (PWH) receiving suppressive antiretroviral therapy (ART)., Design: AIDS Clinical Trials Group A5369 was a phase I/IIa, randomized, double-blind, placebo-controlled study of PWH receiving ART with plasma HIV-1 RNA less than 50 copies/ml, current CD4 + T-cell counts greater than 500 cells/μl, and nadir CD4 + T-cell counts greater than 350 cells/μl., Methods: The study enrolled 45 participants randomized 2 : 1 : 1 to receive p24CE DNA vaccine at weeks 0 and 4, followed by p24CE DNA admixed with full-length p55 Gag DNA vaccine at weeks 12 and 24 (arm A); full-length p55 Gag DNA vaccine at weeks 0, 4, 12, and 24 (arm B); or placebo at weeks 0, 4, 12, and 24 (arm C). The active and placebo vaccines were administered by intramuscular electroporation., Results: There was a modest, but significantly greater increase in the number of conserved elements recognized by CD4 + and/or CD8 + T cells in arm A compared with arm C ( P  = 0.014). The percentage of participants with an increased number of conserved elements recognized by T cells was also highest in arm A (8/18, 44.4%) vs. arm C (0/10, 0.0%) ( P  = 0.025). There were no significant differences between treatment groups in the change in magnitude of responses to total conserved elements., Conclusion: A DNA-delivered HIV-1 Gag conserved element vaccine boosted by a combination of this vaccine with a full-length p55 Gag DNA vaccine induced a new conserved element-directed cellular immune response in approximately half the treated PWH on ART., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Competing Interests: Disclosures R.J.B. reported receiving research grants/grants pending awarded to his institution from Merck & Co, Inc, and serving on the scientific advisory board for Merck & Co, Inc, ViiV Healthcare, Gilead Sciences, Inc, Shionogi, and Janssen Pharmaceuticals. P.T. has received compensation for consultation services from Merck, Gilead, and ViiV Healthcare. Additionally, the University of Pennsylvania has been granted financial support in the form of research grants for conducting HIV-related studies from the National Institutes of Health, Merck, Gilead, ViiV Healthcare, Sangamo, Takeda and Janssen Pharmaceuticals. The other author reports no conflicts.

The persistence of CD4 + T cells carrying latent human immunodeficiency virus-1 (HIV-1) proviruses is the main barrier to a cure. New therapeutics to enhance HIV-1-specific immune responses and clear infected cells will probably be necessary to achieve reduction of the latent reservoir. In the present study, we report two single-chain diabodies (scDbs) that target the HIV-1 envelope protein (Env) and the human type III Fcγ receptor (CD16). We show that the scDbs promoted robust and HIV-1-specific natural killer (NK) cell activation and NK cell-mediated lysis of infected cells. Cocultures of CD4 + T cells from people with HIV-1 on antiretroviral therapy (ART) with autologous NK cells and the scDbs resulted in marked elimination of reservoir cells that was dependent on latency reversal. Treatment of human interleukin-15 transgenic NSG mice with one of the scDbs after ART initiation enhanced NK cell activity and reduced reservoir size. Thus, HIV-1-specific scDbs merit further evaluation as potential therapeutics for clearance of the latent reservoir., (© 2024. The Author(s).)

Background: A feature of HIV cure trials is the need to interrupt treatment to test the efficacy of experimental interventions-a process known as analytical treatment interruptions (ATIs)., Objectives: We report the experiences of participants after they completed an extended ATI., Methods: From April to November 2022, we conducted post-ATI in-depth interviews with BEAT2 clinical trial (NCT03588715) participants who stopped ART while receiving an immunotherapy regimen. We used conventional content analysis to code the data., Results: We conducted interviews with 11 Black/African American and three White/Caucasian participants (11 males, two females, and one transgender woman). The mean ATI was 38 weeks. Participants noted several significant experiences surrounding the interventions' side effects, ATI, and returning to medication. Some participants had positive experiences with their ATI. Other participants were nervous during the ATI. Rising viral loads led some to feel a sense of failure. Although trial experiences were heterogeneous, participants unanimously had positive interactions with the clinical trial staff which facilitated their retention in the trial. Participants shared their experiences with the trial, including changes in expectations, experiences with experimental interventions and procedures, compensation as a measure of respect, effort, transportation, and effects of COVID-19 during the trial. Based on these results, we provide considerations for the conduct of future HIV cure-directed clinical trials involving ATIs., Conclusions: Managing expectations, focusing on participants' contributions, and providing support to reduce feelings of having failed the research team and/or the HIV community following viral rebound should be part of HIV cure trial design. Discussing the mental health impact of rebound during consent, distinct from risk, is needed. Continued efforts to understand how people with HIV experience ATIs will improve future designs of HIV cure clinical trials.

HIV-1 persists in a latent reservoir in resting CD4+ T cells despite antiretroviral therapy (ART). The reservoir decays slowly over the first 7 years of ART (t1/2 = 44 months). However, whether decay continues with long-term ART is unclear. Recent integration site studies indicate gradual selection against inducible, intact proviruses, raising speculation that decades of ART might allow treatment interruption without viral rebound. Therefore, we measured the reservoir in 42 people on long-term ART (mean 22 years) using a quantitative viral outgrowth assay. After 7 years of ART, there was no long-term decrease in the frequency of inducible, replication-competent proviruses but rather an increase with an estimated doubling time of 23 years. Another reservoir assay, the intact proviral DNA assay, confirmed that reservoir decay with t1/2 of 44 months did not continue with long-term ART. The lack of decay reflected proliferation of infected cells. Most inducible, replication-competent viruses (79.8%) had env sequences identical to those of other isolates from the same sample. Thus, although integration site analysis indicates changes in reservoir composition, the proliferation of CD4+ T cells counteracts decay, maintaining the frequency of inducible, replication-competent proviruses at roughly constant levels over the long term. These results reinforce the need for lifelong ART.

The Penn Medicine COVID-19 Therapeutics Committee-an interspecialty, clinician-pharmacist, and specialist-front line primary care collaboration-has served as a forum for rapid evidence review and the production of dynamic practice recommendations during the 3-year coronavirus disease 2019 public health emergency. We describe the process by which the committee went about its work and how it navigated specific challenging scenarios. Our target audiences are clinicians, hospital leaders, public health officials, and researchers invested in preparedness for inevitable future threats. Our objectives are to discuss the logistics and challenges of forming an effective committee, undertaking a rapid evidence review process, aligning evidence-based guidelines with operational realities, and iteratively revising recommendations in response to changing pandemic data. We specifically discuss the arc of evidence for corticosteroids; the noble beginnings and dangerous misinformation end of hydroxychloroquine and ivermectin; monoclonal antibodies and emerging viral variants; and patient screening and safety processes for tocilizumab, baricitinib, and nirmatrelvir-ritonavir., Competing Interests: Potential conflicts of interest. G. L. A. reports additional research support from the CDC Foundation and the Society of Critical Care Medicine. G. L. A. reports payments for authoring chapters for UpToDate and for expert witness consulting, including involving COVID-19, and reports that his spouse is employed by the US Food and Drug Administration. K. D. reports research funding from Gilead Scienes for participation in a clinical trial of remdesivir. All other authors report no potential conflicts., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Analytical treatment interruption (ATI), defined as a closely monitored clinical pause in antiretroviral therapy (ART), is a core component of many HIV cure-directed clinical studies. ATIs may cause significant physical and psychosocial risks for people living with HIV and, as a result, integrating participant and community perspectives into clinical trial designs that include an ATI is crucial to ensuring a successful and person-centered trial. We conducted semi-structured interviews with participants enrolling in the BEAT-2 cure-directed trial (NCT03588715). Interviews elicited participant motivations and decision-making processes for trial participation along with participants' perceptions of the ATI. Interviews were recorded, transcribed, and analyzed using a directed content analysis. Fourteen of 15 trial participants completed interviews. The majority were Black (79%) cisgender male (79%). Participants noted several significant motivating factors contributing to their desire to enroll in the HIV cure-directed clinical trial, the most prominent being a desire to find a cure for HIV and help others in the HIV community. HIV care teams were the most commonly identified resource for patients when making the decision to enroll in the trial, and family, friends, and romantic partners also played a significant role. Altruism was a primary motivation for participation, although participants also shared interest in learning about HIV science and research. Participants had a strong understanding of trial procedures and displayed significant trust in the study team to keep them informed and healthy during their participation. The ATI was a significant source of anxiety for participants. Their primary worry was that their prior antiretroviral therapy (ART) regimen would no longer be effective once they resumed ART. Despite these concerns, participants shared considerable excitement for continued participation in the trial and being a part of the search toward an HIV cure.

Objective: The aim of this study was to assess the susceptibility of HIV to two HIV monoclonal antibodies (bnAbs), 3BNC117 and 10-1074, in individuals with chronically antiretroviral therapy (ART) suppressed HIV infection., Design: The susceptibility of bnAbs was determined using the PhenoSense mAb Assay, which is a cell-based infectivity assay designed to assess the susceptibility of luciferase-reporter pseudovirions. This assay is the only Clinical Laboratory Improvement Ammendment (CLIA)/College of American Pathologist (CAP) compliant screening test specifically developed for evaluating bnAb susceptibility in people with HIV infection., Method: The susceptibility of luciferase-reporter pseudovirions, derived from HIV-1 envelope proteins obtained from peripheral bloodmononuclear cells of 61 ART-suppressed individuals, to 3BNC117 and 10-1074 bnAbs was assessed using the PhenoSense mAb assay. Susceptibility was defined as an IC 90 of <2.0 μg/ml and 1.5 μg/ml for 3BNC117 and 10-1074, respectively., Results: About half of the individuals who were chronically infected and virologically suppressed were found to harbor virus with reduced susceptibility to one or both of the tested bnAbs., Conclusions: The reduced combined susceptibility of 3BNC117 and 10-1074 highlights a potential limitation of using only two bnAbs for pre-exposure prophylaxis or treatment. Further studies are needed to define and validate the clinical correlates of bnAb susceptibility., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: HIV affects 36 million people globally with prevalence decreasing due to antiretroviral therapy (ART) and social awareness; transmission occurs during substance use. Cocaine usage independently affects brain activity and may result in reduced ART adherence. This study evaluates brain glucose metabolism measured by 18 F-fluorodeoxyglucose positron emission tomography/computed tomography ( 18 F-FDG PET/CT) in cocaine users with HIV infection., Design: Sixty-three participants were categorized into groups: 36 HIV infected (HIV+) and 27 non-HIV infected (HIV-) individuals. Each group was further split into cocaine users (CO+) and non-cocaine users (CO-). Of the HIV+, half were cocaine users and half were not. Of the HIV-, 14 were cocaine users and 13 were not. 18 F-FDG-PET and low dose CT scans were performed on all participants., Methods: Brain glucose metabolism was evaluated by 18 F-FDG uptake in the whole brain, cortex, basal ganglia, and cerebellum 120 min after injection. ROVER software was used for image analysis and regions of interest masks were applied via an adaptive threshold system. ANOVA tests and t -tests were performed to assess the respective differences between the four groups., Results: Generally, the HIV+/CO+ group (group A) displayed the lowest levels of uptake whereas the HIV-/CO- group (group D) showed the highest; the HIV+/CO- and HIV-/CO+ groups (groups B and C) showed intermediate levels of activity across the whole brain, cortex, basal ganglia, and cerebellum., Conclusion: HIV infection and cocaine usage were independently associated with a decrease in brain glucose uptake as measured by 18 F-FDG PET/CT. When combined, positive HIV status and cocaine patients showed the most decreased 18 F-FDG uptake., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Cytomegalovirus (CMV) infection is thought to result in increased immune activation in people with human immunodeficiency virus (HIV, PWH). Although some data have linked asymptomatic CMV infection to cardiovascular disease among PWH, it remains unknown whether CMV is associated with increased or high-risk coronary plaque., Methods: The Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) enrolled PWH aged 40-75 years on stable antiretroviral therapy (ART) with low-to-moderate atherosclerotic cardiovascular disease (ASCVD) risk. Among a subset of US REPRIEVE participants, coronary plaque was assessed by coronary computed tomography angiography. Here, we assessed the relationship between CMV immunoglobulin G (IgG) titer and (1) levels of immune activation, (2) inflammatory biomarkers, and (3) coronary plaque phenotypes at study entry., Results: Of 672 participants, mean age was 51 years, 83% were men, median ASCVD risk score was 4.5%, and 66% had current CD4+ T-cell count ≥500 cells/mm3. Higher CMV IgG quartile group was associated with older age and lower current and nadir CD4+ T-cell counts. CMV IgG titer was associated with specific inflammatory biomarkers (sCD163, MCP-1, interleukin [IL]-6, hsCRP) in univariate analysis, but not after controlling for HIV-specific factors. In contrast, CMV IgG titer was not associated with coronary artery disease indexes, including presence of plaque, coronary artery calcium (CAC) score >0, vulnerable plaque presence, or Leaman score >5., Conclusions: No meaningful association was seen between CMV IgG titer and coronary artery disease indexes among ART-treated PWH at study enrollment. Longitudinal assessments in REPRIEVE will determine the relationship of CMV IgG titer to plaque progression and cardiovascular events., Clinical Trials Registration: NCT02344290., Competing Interests: Potential conflicts of interest. The views expressed in this article are those of the authors and do not necessarily represent the views of the NHLBI, the NIAID, the NIH, or the US Department of Health and Human Services. S. R. S. reports grant support through his institution from NIH/NIAID. M. T. L. reports grant support through his institution from Kowa Pharmaceuticals America, Inc, for the conduct of the study. He also reports grant support from MedImmune/Astrazeneca and personal fees from PQBypass outside of the current work. T. H. B. reports equity in Excision BioTherapeutics and serves on their Scientific Advisory Board, outside the submitted work. M. V. Z. reports grant support through her institution from NIH/NIAID and Gilead Sciences, Inc, relevant to the conduct of the study, as well as grants from NIH/NIAID and NIH/NHLBI outside the submitted work: RO1AI123001 PI, U01HL123336 Co-I, R01 HL137562 PI, U01HL123336-06S2 Co-I, R01HL146267 PI, R01HL151283 Co-I, K24AI157882 PI. M. V. Z. also reports support for attending meetings and/or travel from CROI and International Workshop for HIV and Women from conference organizing committee when abstract reviewer and/or speaker; unpaid participation on DSMB for NIH funded studies. B. F. reports unrelated grant support paid to institution from NIH/NHLBI, MedImmune/Astrazeneca, and MedTrace. C. M. reports grants to institution from Gilead Sciences, unrelated to this work, participation on Advisory Boards for ViiV Healthcare and Gilead Sciences, and no other disclosures. C. J. F. reports grant support through his institution from Gilead Sciences, ViiV Healthcare, GSK, Janssen, Abbvie, Merck, Amgen, and Cytodyn, outside the submitted work, and participation as Chair of DSMB for Intrepid Study. J. A. A. reports institutional research support for clinical trials from Atea, Emergent Biosolutions, Frontier Technologies, Gilead Sciences, Glaxo Smith Kline, Janssen, Merck, Pfizer, Regeneron, and ViiV Healthcare and personal fees for advisory boards from Glaxo Smith Kline/ViiV and Merck, and participation on a DSMB for Kintor; all outside the submitted work. E. T. O. reports grant support through his institution from NIH, Gilead, ViiV, and GSK, personal fees from Merck, ViiV Healthcare, and Theratechnologies, outside the submitted work, and roles as chair of Comorbidity Transformational Science Group for NIH-funded ACTG and as member of Scientific Review Committee for NIH-funded HVTN. J. C. reports consulting fees from Merck and Company (11/2021) and Resvirlogix. B. E. S. reports grant support through her institution from ViiV Healthcare and Gilead (Focus grant) outside the submitted work. H. J. R. reports grants from NIH/NIAID and NIH/NHLBI during the conduct of the study, as well as grants from NIH/NIAID, NIH/NHLBI, NIH/NIDDK, and NIH/NIA, outside the submitted work. K. M. E. reports grant support from Gilead Sciences, Inc., and consulting fees from Gilead Sciences, Inc, ViiV Pharmaceuticals America, Inc., and Janssen Therapeutics (all paid to the University of Colorado), and participation on DSMB for NIH study (paid to institution), outside the submitted work. S. K. G. reports grant support through his institution from Kowa Pharmaceuticals America, Inc, Gilead Sciences, Inc, and ViiV Healthcare for the conduct of the study, as well as grants from Theratechnologies and Navidea and personal fees from Theratechnologies Consulting and ViiV Consulting and Navidea, all outside the submitted work. 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.)

Understanding the complexity of the long-lived HIV reservoir during antiretroviral therapy (ART) remains a considerable impediment in research towards a cure for HIV. To address this, we developed a single-cell strategy to precisely define the unperturbed peripheral blood HIV-infected memory CD4 + T cell reservoir from ART-treated people living with HIV (ART-PLWH) via the presence of integrated accessible proviral DNA in concert with epigenetic and cell surface protein profiling. We identified profound reservoir heterogeneity within and between ART-PLWH, characterized by new and known surface markers within total and individual memory CD4 + T cell subsets. We further uncovered new epigenetic profiles and transcription factor motifs enriched in HIV-infected cells that suggest infected cells with accessible provirus, irrespective of reservoir distribution, are poised for reactivation during ART treatment. Together, our findings reveal the extensive inter- and intrapersonal cellular heterogeneity of the HIV reservoir, and establish an initial multiomic atlas to develop targeted reservoir elimination strategies., (© 2022. The Author(s).)

Background: The COVID-19 standard of care (SOC) evolved rapidly during 2020 and 2021, but its cumulative effect over time is unclear., Objective: To evaluate whether recovery and mortality improved as SOC evolved, using data from ACTT (Adaptive COVID-19 Treatment Trial)., Design: ACTT is a series of phase 3, randomized, double-blind, placebo-controlled trials that evaluated COVID-19 therapeutics from February 2020 through May 2021. ACTT-1 compared remdesivir plus SOC to placebo plus SOC, and in ACTT-2 and ACTT-3, remdesivir plus SOC was the control group. This post hoc analysis compared recovery and mortality between these comparable sequential cohorts of patients who received remdesivir plus SOC, adjusting for baseline characteristics with propensity score weighting. The analysis was repeated for participants in ACTT-3 and ACTT-4 who received remdesivir plus dexamethasone plus SOC. Trends in SOC that could explain outcome improvements were analyzed. (ClinicalTrials.gov: NCT04280705 [ACTT-1], NCT04401579 [ACTT-2], NCT04492475 [ACTT-3], and NCT04640168 [ACTT-4])., Setting: 94 hospitals in 10 countries (86% U.S. participants)., Participants: Adults hospitalized with COVID-19., Intervention: SOC., Measurements: 28-day mortality and recovery., Results: Although outcomes were better in ACTT-2 than in ACTT-1, adjusted hazard ratios (HRs) were close to 1 (HR for recovery, 1.04 [95% CI, 0.92 to 1.17]; HR for mortality, 0.90 [CI, 0.56 to 1.40]). Comparable patients were less likely to be intubated in ACTT-2 than in ACTT-1 (odds ratio, 0.75 [CI, 0.53 to 0.97]), and hydroxychloroquine use decreased. Outcomes improved from ACTT-2 to ACTT-3 (HR for recovery, 1.43 [CI, 1.24 to 1.64]; HR for mortality, 0.45 [CI, 0.21 to 0.97]). Potential explanatory factors (SOC trends, case surges, and variant trends) were similar between ACTT-2 and ACTT-3, except for increased dexamethasone use (11% to 77%). Outcomes were similar in ACTT-3 and ACTT-4. Antibiotic use decreased gradually across all stages., Limitation: Unmeasured confounding., Conclusion: Changes in patient composition explained improved outcomes from ACTT-1 to ACTT-2 but not from ACTT-2 to ACTT-3, suggesting improved SOC. These results support excluding nonconcurrent controls from analysis of platform trials in rapidly changing therapeutic areas., Primary Funding Source: National Institute of Allergy and Infectious Diseases.

Background: People with HIV (PWH) and community members have advocated for the development of a home-based viral load test device that could make analytical treatment interruptions (ATIs) less burdensome., Objective: We assessed community acceptability of a novel home-based viral load test device., Methods: In 2021, we conducted 15 interviews and 3 virtual focus groups with PWH involved in HIV cure research. We used conventional thematic analysis to analyze the data., Results: PWH viewed the home-based viral load test device as a critical adjunct in ongoing HIV cure trials with ATIs. The ability to test for viral load at home on demand would alleviate anxiety around being off ART. Participants drew parallels with glucometers used for diabetes. A preference was expressed for the home-based test to clearly indicate whether one was detectable or undetectable for HIV to mitigate risk of HIV transmission to partners. Perceived advantages of the device included convenience, sense of control, and no puncturing of veins. Perceived concerns were possible physical marks, user errors and navigating the logistics of mailing samples to a laboratory and receiving test results. Participants expressed mixed effects on stigma, such as helping normalize HIV, but increased potential for inadvertent disclosure of HIV status or ATI participation. Increasing pluri-potency of the device beyond viral load testing (e.g., CD4+ count test) would increase its utility. Participants suggested pairing the device with telemedicine and mobile health technologies., Conclusions: If proven effective, the home-based viral load test device will become a critical adjunct in HIV cure research and HIV care.

Coronavirus disease 2019 (COVID-19) convalescent plasma (CCP), a passive polyclonal antibody therapeutic agent, has had mixed clinical results. Although antibody neutralization is the predominant approach to benchmarking CCP efficacy, CCP may also influence the evolution of the endogenous antibody response. Using systems serology to comprehensively profile severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) functional antibodies of hospitalized people with COVID-19 enrolled in a randomized controlled trial of CCP (ClinicalTrials.gov: NCT04397757), we find that the clinical benefits of CCP are associated with a shift toward reduced inflammatory Spike (S) responses and enhanced nucleocapsid (N) humoral responses. We find that CCP has the greatest clinical benefit in participants with low pre-existing anti-SARS-CoV-2 antibody function and that CCP-induced immunomodulatory Fc glycan profiles and N immunodominant profiles persist for at least 2 months. We highlight a potential mechanism of action of CCP associated with durable immunomodulation, outline optimal patient characteristics for CCP treatment, and provide guidance for development of a different class of COVID-19 hyperinflammation-targeting antibody therapeutic agents., Competing Interests: Declaration of interests G.A. is a founder of SeromYx Systems, Inc., an equity holder in Leyden Labs, and a member of the scientific advisory board of Sanofi Pasteur., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Monoclonal antibody therapy has played an important role against SARS-CoV-2. Strategies to deliver functional, antibody-based therapeutics with improved in vivo durability are needed to supplement current efforts and reach underserved populations. Here, we compare recombinant mAbs COV2-2196 and COV2-2130, which compromise clinical cocktail Tixagevimab/Cilgavimab, with optimized nucleic acid-launched forms. Functional profiling of in vivo-expressed, DNA-encoded monoclonal antibodies (DMAbs) demonstrated similar specificity, broad antiviral potency and equivalent protective efficacy in multiple animal challenge models of SARS-CoV-2 prophylaxis compared to protein delivery. In PK studies, DNA-delivery drove significant serum antibody titers that were better maintained compared to protein administration. Furthermore, cryo-EM studies performed on serum-derived DMAbs provide the first high-resolution visualization of in vivo-launched antibodies, revealing new interactions that may promote cooperative binding to trimeric antigen and broad activity against VoC including Omicron lineages. These data support the further study of DMAb technology in the development and delivery of valuable biologics., (© 2022. The Author(s).)

Because oral transmission of SARS-CoV-2 is 3-5 orders of magnitude higher than nasal transmission, we investigated debulking of oral viruses using viral trap proteins (CTB-ACE2, FRIL) expressed in plant cells, delivered through the chewing gum. In omicron nasopharyngeal (NP) samples, the microbubble count (based on N-antigen) was significantly reduced by 20 μg of FRIL (p < 0.0001) and 0.925 μg of CTB-ACE2 (p = 0.0001). Among 20 delta or omicron NP samples, 17 had virus load reduced below the detection level of spike protein in the RAPID assay, after incubation with the CTB-ACE2 gum powder. A dose-dependent 50% plaque reduction with 50-100 ng FRIL or 600-800 μg FRIL gum against Influenza strains H1N1, H3N2, and Coronavirus HCoV-OC43 was observed with both purified FRIL, lablab bean powder or gum. In electron micrographs, large/densely packed clumps of overlapping influenza particles and FRIL protein were observed. Chewing simulator studies revealed that CTB-ACE2 release was time/dose-dependent and release was linear up to 20 min chewing. Phase I/II placebo-controlled, double-blinded clinical trial (IND 154897) is in progress to evaluate viral load in saliva before or after chewing CTB-ACE2/placebo gum. Collectively, this study advances the concept of chewing gum to deliver proteins to debulk oral viruses and decrease infection/transmission., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Henry Daniell has patent #USA patent 11,246,819 issued to University of Pennsylvania. Henry Daniell has patent #USA patent 10,806,775 issued to University of Pennsylvania. Henry Daniell has patent #USA patent 10,314,893 issued to University of Pennsylvania., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background : HIV cure-directed clinical trials using analytical treatment interruptions (ATIs) require participants to adhere to frequent monitoring visits for viral load tests. Novel viral load monitoring strategies are needed to decrease participant burden during ATIs. Objective : To examine acceptability of a novel home-based blood collection device for viral load testing in the context of two ongoing ATI trials in Philadelphia, PA, United States. Methods : From January 2021 to February 2022, participants completed three in-depth interviews via teleconference during their participation in an ATI: (1) within two weeks of enrollment in the device study, (2) approximately four weeks after beginning to use the device, and (3) within two weeks of the end of the ATI when ART was re-initiated. We used conventional content analysis to analyze the data. Results : We recruited 17 participants: 15 were cisgender males, 1 cisgender female, and 1 transgender woman. We observed an overall 87% success rate in drawing blood with the device from home collection and found overall high acceptance of the device. A mean of 91.5 devices per participant were used for home-based blood collection. Most PWH viewed the device as relatively convenient, painless, easy to use, and a simple solution to frequent blood draws. The main challenge encountered was the inability to completely fill up devices with blood in some cases. Most participants reported positive experiences with mailing blood samples and could see themselves using the device on a regular basis outside of ATIs. Conclusions : Our study showed participant valued the novel home-based peripheral blood collection for viral load testing in the context of ATI trials. More research will be necessary to optimize implementation of the device and to assess whether blood collected can reliably measure viral loads in the context of ATI trials.

Despite effective antiretroviral therapy, HIV-1 persistence in latent reservoirs remains a major obstacle to a cure. We postulate that HIV-1 silencing factors suppress HIV-1 reactivation and that inhibition of these factors will increase HIV-1 reactivation. To identify HIV-1 silencing factors, we conducted a genome-wide CRISPR inhibition (CRISPRi) screen using four CRISPRi-ready, HIV-1-d6-GFP-infected Jurkat T cell clones with distinct integration sites. We sorted cells with increased green fluorescent protein (GFP) expression and captured single guide RNAs (sgRNAs) via targeted deep sequencing. We identified 18 HIV-1 silencing factors that were significantly enriched in HIV-1-d6-GFP high cells. Among them, SLTM (scaffold attachment factor B-like transcription modulator) is an epigenetic and transcriptional modulator having both DNA and RNA binding capacities not previously known to affect HIV-1 transcription. Knocking down SLTM by CRISPRi significantly increased HIV-1-d6-GFP expression (by 1.9- to 4.2-fold) in three HIV-1-d6-GFP-Jurkat T cell clones. Furthermore, SLTM knockdown increased the chromatin accessibility of HIV-1 and the gene in which HIV-1 is integrated but not the housekeeping gene POLR2A . To test whether SLTM inhibition can reactivate HIV-1 and further induce cell death of HIV-1-infected cells ex vivo , we established a small interfering RNA (siRNA) knockdown method that reduced SLTM expression in CD4 + T cells from 10 antiretroviral therapy (ART)-treated, virally suppressed, HIV-1-infected individuals ex vivo . Using limiting dilution culture, we found that SLTM knockdown significantly reduced the frequency of HIV-1-infected cells harboring inducible HIV-1 by 62.2% (0.56/10 6 versus 1.48/10 6 CD4 + T cells [ P  = 0.029]). Overall, our study indicates that SLTM inhibition reactivates HIV-1 in vitro and induces cell death of HIV-1-infected cells ex vivo . Our study identified SLTM as a novel therapeutic target. IMPORTANCE HIV-1-infected cells, which can survive drug treatment and immune cell killing, prevent an HIV-1 cure. Immune recognition of infected cells requires HIV-1 protein expression; however, HIV-1 protein expression is limited in infected cells after long-term therapy. The ways in which the HIV-1 provirus is blocked from producing protein are unknown. We identified a new host protein that regulates HIV-1 gene expression. We also provided a new method of studying HIV-1-host factor interactions in cells from infected individuals. These improvements may enable future strategies to reactivate HIV-1 in infected individuals so that infected cells can be killed by immune cells, drug treatment, or the virus itself.

Background: The Adaptive Coronavirus Disease 2019 (COVID-19) Treatment Trial-1 (ACTT-1) found that remdesivir therapy hastened recovery in patients hospitalized with COVID-19, but the pathway for this improvement was not explored. We investigated how the dynamics of clinical progression changed along 4 pathways: recovery, improvement in respiratory therapy requirement, deterioration in respiratory therapy requirement, and death., Methods: We analyzed trajectories of daily ordinal severity scores reflecting oxygen requirements of 1051 patients hospitalized with COVID-19 who participated in ACTT-1. We developed competing risks models that estimate the effect of remdesivir therapy on cumulative incidence of clinical improvement and deterioration, and multistate models that utilize the entirety of each patient's clinical course to characterize the effect of remdesivir on progression along the 4 pathways above., Results: Based on a competing risks analysis, remdesivir reduced clinical deterioration (hazard ratio [HR], 0.73; 95% confidence interval [CI]: .59-.91) and increased clinical improvement (HR, 1.22; 95% CI: 1.08, 1.39) relative to baseline. Our multistate models indicate that remdesivir inhibits worsening to ordinal scores of greater clinical severity among patients on room air or low-flow oxygen (HR, 0.74; 95% CI: .57-.94) and among patients receiving mechanical ventilation or high-flow oxygen/noninvasive positive-pressure ventilation (HR, 0.73; 95% CI: .53-1.00) at baseline. We also find that remdesivir reduces expected intensive care respiratory therapy utilization among patients not mechanically ventilated at baseline., Conclusions: Remdesivir speeds time to recovery by preventing worsening to clinical states that would extend the course of hospitalization and increase intensive respiratory support, thereby reducing the overall demand for hospital care., (Published by Oxford University Press for the Infectious Diseases Society of America 2021.)

Understanding the drivers and markers of clonally expanding HIV-1-infected CD4 + T cells is essential for HIV-1 eradication. We used single-cell ECCITE-seq, which captures surface protein expression, cellular transcriptome, HIV-1 RNA, and TCR sequences within the same single cell to track clonal expansion dynamics in longitudinally archived samples from six HIV-1-infected individuals (during viremia and after suppressive antiretroviral therapy) and two uninfected individuals, in unstimulated conditions and after CMV and HIV-1 antigen stimulation. Despite antiretroviral therapy, persistent antigen and TNF responses shaped T cell clonal expansion. HIV-1 resided in Th1-polarized, antigen-responding T cells expressing BCL2 and SERPINB9 that may resist cell death. HIV-1 RNA + T cell clones were larger in clone size, established during viremia, persistent after viral suppression, and enriched in GZMB + cytotoxic effector memory Th1 cells. Targeting HIV-1-infected cytotoxic CD4 + T cells and drivers of clonal expansion provides another direction for HIV-1 eradication., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

BACKGROUNDCOVID-19 remains a global health emergency with limited treatment options, lagging vaccine rates, and inadequate healthcare resources in the face of an ongoing calamity. The disease is characterized by immune dysregulation and cytokine storm. Cyclosporine A (CSA) is a calcineurin inhibitor that modulates cytokine production and may have direct antiviral properties against coronaviruses.METHODSTo test whether a short course of CSA was safe in patients with COVID-19, we treated 10 hospitalized, oxygen-requiring, noncritically ill patients with CSA (starting at a dose of 9 mg/kg/d). We evaluated patients for clinical response and adverse events, measured serum cytokines and chemokines associated with COVID-19 hyperinflammation, and conducted gene-expression analyses.RESULTSFive participants experienced adverse events, none of which were serious; transaminitis was most common. No participant required intensive care unit-level care, and all patients were discharged alive. CSA treatment was associated with significant reductions in serum cytokines and chemokines important in COVID-19 hyperinflammation, including CXCL10. Following CSA administration, we also observed a significant reduction in type I IFN gene expression signatures and other transcriptional profiles associated with exacerbated hyperinflammation in the peripheral blood cells of these patients.CONCLUSIONShort courses of CSA appear safe and feasible in patients with COVID-19 who require oxygen and may be a useful adjunct in resource-limited health care settings.TRIAL REGISTRATIONThis trial was registered on ClinicalTrials.gov (Investigational New Drug Application no. 149997; ClinicalTrials.gov NCT04412785).FUNDINGThis study was internally funded by the Center for Cellular Immunotherapies.

Background: Additional severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines that are safe and effective as primary vaccines and boosters remain urgently needed to combat the coronavirus disease 2019 (COVID-19) pandemic. We describe safety and durability of immune responses following 2 primary doses and a homologous booster dose of an investigational DNA vaccine (INO-4800) targeting full-length spike antigen., Methods: Three dosage strengths of INO-4800 (0.5 mg, 1.0 mg, and 2.0 mg) were evaluated in 120 age-stratified healthy adults. Intradermal injection of INO-4800 followed by electroporation at 0 and 4 weeks preceded an optional booster 6-10.5 months after the second dose., Results: INO-4800 appeared well tolerated with no treatment-related serious adverse events. Most adverse events were mild and did not increase in frequency with age and subsequent dosing. A durable antibody response was observed 6 months following the second dose; a homologous booster dose significantly increased immune responses. Cytokine-producing T cells and activated CD8+ T cells with lytic potential were significantly increased in the 2.0-mg dose group., Conclusions: INO-4800 was well tolerated in a 2-dose primary series and homologous booster in all adults, including elderly participants. These results support further development of INO-4800 for use as primary vaccine and booster., Clinical Trials Registration: NCT04336410., (© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: The Adaptive COVID Treatment Trial-2 (ACTT-2) found that baricitinib in combination with remdesivir therapy (BCT) sped recovery in hospitalized coronavirus disease 2019 (COVID-19) patients vs remdesivir monotherapy (RMT). We examined how BCT affected progression throughout hospitalization and utilization of intensive respiratory therapies., Methods: We characterized the clinical trajectories of 891 ACTT-2 participants requiring supplemental oxygen or higher levels of respiratory support at enrollment. We estimated the effect of BCT on cumulative incidence of clinical improvement and deterioration using competing risks models. We developed multistate models to estimate the effect of BCT on clinical improvement and deterioration and on utilization of respiratory therapies., Results: BCT resulted in more linear improvement and lower incidence of clinical deterioration compared with RMT (hazard ratio [HR], 0.74; 95% CI, 0.58 to 0.95). The benefit was pronounced among participants enrolled on high-flow oxygen or noninvasive positive-pressure ventilation. In this group, BCT sped clinical improvement (HR, 1.21; 95% CI, 0.99 to 1.51) while slowing clinical deterioration (HR, 0.71; 95% CI, 0.48 to 1.02), which reduced the expected days in ordinal score (OS) 6 per 100 patients by 74 days (95% CI, -8 to 154 days) and the expected days in OS 7 per 100 patients by 161 days (95% CI, 46 to 291 days) compared with RMT. BCT did not benefit participants who were mechanically ventilated at enrollment., Conclusions: Compared with RMT, BCT reduces the clinical burden and utilization of intensive respiratory therapies for patients requiring low-flow oxygen or noninvasive positive-pressure ventilation compared with RMT and may thereby improve care for this patient population., (Published by Oxford University Press on behalf of Infectious Diseases Society of America. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Background: Despite widespread availability of direct-acting antivirals including generic formulations, limited progress has been made in the global adoption of hepatitis C virus (HCV) treatment. Barriers to treatment scale-up include availability and access to diagnostic and monitoring tests, health-care infrastructure, and requirement for frequent visits during treatment., Methods: ACTG A5360 was a phase 4, open-label, single-arm trial across 38 sites in Brazil, South Africa, Thailand, Uganda, and the USA. Key inclusion criteria were age of 18 years or older, evidence of active HCV infection (HCV RNA >1000 IU/mL) and HCV treatment-naive; patients with compensated cirrhosis and HIV/HCV co-infection were included but their enrolment was capped. All participants received a fixed dose combination of oral sofosbuvir (400 mg) and velpatasvir (100 mg) once daily for 12 weeks. The minimal monitoring (MINMON) approach consisted of four components: (1) there was no pre-treatment genotyping; (2) the entire treatment course (84 tablets) was dispensed at entry; (3) there were no scheduled visits or laboratory monitoring; and (4) there were two points of remote contact, at week 4 for adherence and week 22, to schedule outcome assessment at week 24 (-2 weeks to +4 weeks). Participants who missed the week 24 window could return for a visit to assess treatment response any time before week 72. Unplanned visits for any reason were permissible before the week 24 visit. The primary efficacy outcome was sustained virological response (SVR), defined as HCV RNA less than the lower limit of quantification measured at least 22 weeks post-treatment initiation; the primary safety outcome was serious adverse events. The primary efficacy analysis included all participants who initiated treatment, using a missing=failure approach. The primary safety analysis included all participants who initiated treatment and had at least one post-treatment assessment. This trial is registered at ClinicalTrials.gov, NCT03512210., Findings: Between Oct 22, 2018, and July 19, 2019, 400 participants were enrolled across all 38 sites; 399 initiated treatment. At the SVR assessment visit, 355 (89%) of 397 participants reported taking 100% of the trial medication during the 12-week treatment period; two patients did not have any follow-up visits after the entry visit and were excluded from the safety analyses. Overall, 379 of the 399 who initiated treatment had an SVR (95·0%, 95% CI 92·4-96·7). 14 (4%) of 397 participants reported serious adverse events between treatment initiation and week 28; none were treatment related or led to treatment discontinuation or death. 15 (4%) of 399 participants had unplanned visits; none were related to treatment., Interpretation: In this diverse global population of people with HCV, the MINMON approach with sofosbuvir-velpatasvir treatment was safe and achieved SVR comparable to standard monitoring observed in real-world data. Coupled with innovative case finding strategies, this strategy could be crucial to the global HCV elimination agenda., Funding: US National Institutes of Health and Gilead Sciences., Competing Interests: Declaration of interests SSS declares grants and study products to the institution from Gilead Sciences related to the submitted work as well as grants and study product to the institution from Gilead Sciences and Abbott Laboratories not related to the submitted work, and honoraria from Gilead Sciences. GKR declares grants to his institution from Gilead Sciences, Citius Pharmaceuticals, Pfizer, Emergent Biosolutions, and Leonard Meron Bioscience, outside of the submitted work, and consulting fees from Teradyne Inc, Massachusetts Executive Office of Energy and Environmental Affairs, and Massachusetts Interscholastic Athletic Association. AS and NC are employees of Gilead Sciences and hold stock in the company. EPN declares honoraria from Gilead and AbbVie. DK declares honoraria and support to attend conferences from Gilead Sciences. JS declares speaker and advisory board honoraria from ViiV, Merck, Gilead, and AbbVie. PT declares consulting fees from ViiV and Merck. CB declares grants from Gilead Sciences paid to her institution, outside of the submitted work, and served as the chair of a data safety and monitoring board (DSMB) for GlaxoSmithKline. SN declares grants from Gilead Sciences and AbbVie to her institution, outside of the submitted work, personal consulting fees from BioMarin and Theratechnologies, support to attend meetings from Gilead Sciences, and has participated on DSMB for Bristol Myers Squibb, FHI 360, and Personal Health Insights Inc, and holds stock options in Vir Bio. DW declares grants to his institution from Gilead Sciences outside of the submitted work and discloses royalties/licenses from UpToDate. MS declares grants to his institution from Gilead Sciences, AbbVie, Janssen, and Assembly Biosciences outside of the submitted work, personal consulting fees from AbbVie, Gilead Sciences, Assembly Biosciences, Arbutus, Virion, Antios, and GlaxoSmithKline, has received honoraria from Practice Point Communication, DKB, and Clinical Care Options, and served on DSMBs and holds stock in Gilead Sciences and AbbVie. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Frequent viral load testing is necessary during analytical treatment interruptions (ATIs) in HIV cure-directed clinical trials, though such may be burdensome and inconvenient to trial participants. We implemented a national, cross-sectional survey in the United States to examine the acceptability of a novel home-based peripheral blood collection device for HIV viral load testing. Between June and August 2021, we distributed an online survey to people with HIV (PWH) and community members, biomedical HIV cure researchers and HIV care providers. We performed descriptive analyses to summarize the results. We received 73 survey responses, with 51 from community members, 12 from biomedical HIV cure researchers and 10 from HIV care providers. Of those, 51 (70%) were cisgender men and 50 (68%) reported living with HIV. Most (>80% overall) indicated that the device would be helpful during ATI trials and they would feel comfortable using it themselves or recommending it to their patients/participants. Of the 50 PWH, 42 (84%) indicated they would use the device if they were participating in an ATI trial and 27 (54%) also expressed a willingness to use the device outside of HIV cure studies. Increasing sensitivity of viral load tests and pluri-potency of the device (CD4 count, chemistries) would augment acceptability. Survey findings provide evidence that viral load home testing would be an important adjunct to ongoing HIV cure-directed trials involving ATIs. Survey findings may help inform successful implementation and uptake of the device in the context of personalized HIV care.

Importance: COVID-19 convalescent plasma (CCP) is a potentially beneficial treatment for COVID-19 that requires rigorous testing., Objective: To compile individual patient data from randomized clinical trials of CCP and to monitor the data until completion or until accumulated evidence enables reliable conclusions regarding the clinical outcomes associated with CCP., Data Sources: From May to August 2020, a systematic search was performed for trials of CCP in the literature, clinical trial registry sites, and medRxiv. Domain experts at local, national, and international organizations were consulted regularly., Study Selection: Eligible trials enrolled hospitalized patients with confirmed COVID-19, not receiving mechanical ventilation, and randomized them to CCP or control. The administered CCP was required to have measurable antibodies assessed locally., Data Extraction and Synthesis: A minimal data set was submitted regularly via a secure portal, analyzed using a prespecified bayesian statistical plan, and reviewed frequently by a collective data and safety monitoring board., Main Outcomes and Measures: Prespecified coprimary end points-the World Health Organization (WHO) 11-point ordinal scale analyzed using a proportional odds model and a binary indicator of WHO score of 7 or higher capturing the most severe outcomes including mechanical ventilation through death and analyzed using a logistic model-were assessed clinically at 14 days after randomization., Results: Eight international trials collectively enrolled 2369 participants (1138 randomized to control and 1231 randomized to CCP). A total of 2341 participants (median [IQR] age, 60 [50-72] years; 845 women [35.7%]) had primary outcome data as of April 2021. The median (IQR) of the ordinal WHO scale was 3 (3-6); the cumulative OR was 0.94 (95% credible interval [CrI], 0.74-1.19; posterior probability of OR <1 of 71%). A total of 352 patients (15%) had WHO score greater than or equal to 7; the OR was 0.94 (95% CrI, 0.69-1.30; posterior probability of OR <1 of 65%). Adjusted for baseline covariates, the ORs for mortality were 0.88 at day 14 (95% CrI, 0.61-1.26; posterior probability of OR <1 of 77%) and 0.85 at day 28 (95% CrI, 0.62-1.18; posterior probability of OR <1 of 84%). Heterogeneity of treatment effect sizes was observed across an array of baseline characteristics., Conclusions and Relevance: This meta-analysis found no association of CCP with better clinical outcomes for the typical patient. These findings suggest that real-time individual patient data pooling and meta-analysis during a pandemic are feasible, offering a model for future research and providing a rich data resource.

BackgroundAntibody-based strategies for COVID-19 have shown promise in prevention and treatment of early disease. COVID-19 convalescent plasma (CCP) has been widely used but results from randomized trials supporting its benefit in hospitalized patients with pneumonia are limited. Here, we assess the efficacy of CCP in severely ill, hospitalized adults with COVID-19 pneumonia.MethodsWe performed a randomized control trial (PennCCP2), with 80 adults hospitalized with COVID-19 pneumonia, comparing up to 2 units of locally sourced CCP plus standard care versus standard care alone. The primary efficacy endpoint was comparison of a clinical severity score. Key secondary outcomes include 14- and 28-day mortality, 14- and 28-day maximum 8-point WHO ordinal score (WHO8) score, duration of supplemental oxygenation or mechanical ventilation, respiratory SARS-CoV-2 RNA, and anti-SARS-CoV-2 antibodies.ResultsEighty hospitalized adults with confirmed COVID-19 pneumonia were enrolled at median day 6 of symptoms and day 1 of hospitalization; 60% were anti-SARS-CoV-2 antibody seronegative. Participants had a median of 3 comorbidities, including risk factors for severe COVID-19 and immunosuppression. CCP treatment was safe and conferred significant benefit by clinical severity score (median [MED] and interquartile range [IQR] 10 [5.5-30] vs. 7 [2.75-12.25], P = 0.037) and 28-day mortality (n = 10, 26% vs. n = 2, 5%; P = 0.013). All other prespecified outcome measures showed weak evidence toward benefit of CCP.ConclusionTwo units of locally sourced CCP administered early in hospitalization to majority seronegative participants conferred a significant benefit in clinical severity score and 28-day mortality. Results suggest CCP may benefit select populations, especially those with comorbidities who are treated early.Trial RegistrationClinicalTrials.gov NCT04397757.FundingUniversity of Pennsylvania.

Antivirals are urgently needed to combat the global SARS-CoV-2/COVID-19 pandemic, supplement existing vaccine efforts, and target emerging SARS-CoV-2 variants of concern. Small molecules that interfere with binding of the viral spike receptor binding domain (RBD) to the host angiotensin-converting enzyme II (ACE2) receptor may be effective inhibitors of SARS-CoV-2 cell entry. Here, we screened 512 pure compounds derived from natural products using a high-throughput RBD/ACE2 binding assay and identified (-)-hopeaphenol, a resveratrol tetramer, in addition to vatalbinoside A and vaticanol B, as potent and selective inhibitors of RBD/ACE2 binding and viral entry. For example, (-)-hopeaphenol disrupted RBD/ACE2 binding with a 50% inhibitory concentration (IC 50 ) of 0.11 μM, in contrast to an IC 50 of 28.3 μM against the unrelated host ligand/receptor binding pair PD-1/PD-L1 (selectivity index, 257.3). When assessed against the USA-WA1/2020 variant, (-)-hopeaphenol also inhibited entry of a VSVΔG-GFP reporter pseudovirus expressing SARS-CoV-2 spike into ACE2-expressing Vero-E6 cells and in vitro replication of infectious virus in cytopathic effect and yield reduction assays (50% effective concentrations [EC 50 s], 10.2 to 23.4 μM) without cytotoxicity and approaching the activities of the control antiviral remdesivir (EC 50 s, 1.0 to 7.3 μM). Notably, (-)-hopeaphenol also inhibited two emerging variants of concern, B.1.1.7/Alpha and B.1.351/Beta in both viral and spike-containing pseudovirus assays with similar or improved activities over the USA-WA1/2020 variant. These results identify (-)-hopeaphenol and related stilbenoid analogues as potent and selective inhibitors of viral entry across multiple SARS-CoV-2 variants of concern.

Global surveillance has identified emerging SARS-CoV-2 variants of concern (VOC) associated with broadened host specificity, pathogenicity, and immune evasion to vaccine-induced immunity. Here we compared humoral and cellular responses against SARS-CoV-2 VOC in subjects immunized with the DNA vaccine, INO-4800. INO-4800 vaccination induced neutralizing antibodies against all variants tested, with reduced levels detected against B.1.351. IFNγ T cell responses were fully maintained against all variants tested., (© 2021. The Author(s).)

Background: Although Zika virus (ZIKV) infection is typically self-limiting, other associated complications such as congenital birth defects and the Guillain-Barré syndrome are well described. There are no approved vaccines against ZIKV infection., Methods: In this phase 1, open-label clinical trial, we evaluated the safety and immunogenicity of a synthetic, consensus DNA vaccine (GLS-5700) encoding the ZIKV premembrane and envelope proteins in two groups of 20 participants each. The participants received either 1 mg or 2 mg of vaccine intradermally, with each injection followed by electroporation (the use of a pulsed electric field to introduce the DNA sequence into cells) at baseline, 4 weeks, and 12 weeks., Results: The median age of the participants was 38 years, and 60% were women; 78% were White and 22% Black; in addition, 30% were Hispanic. At the interim analysis at 14 weeks (i.e., after the third dose of vaccine), no serious adverse events were reported. Local reactions at the vaccination site (e.g., injection-site pain, redness, swelling, and itching) occurred in approximately 50% of the participants. After the third dose of vaccine, binding antibodies (as measured on enzyme-linked immunosorbent assay) were detected in all the participants, with geometric mean titers of 1642 and 2871 in recipients of 1 mg and 2 mg of vaccine, respectively. Neutralizing antibodies developed in 62% of the samples on Vero-cell assay. On neuronal-cell assay, there was 90% inhibition of ZIKV infection in 70% of the serum samples and 50% inhibition in 95% of the samples. The intraperitoneal injection of postvaccination serum protected 103 of 112 IFNAR knockout mice (bred with deletion of genes encoding interferon-α and interferon-β receptors) (92%) that were challenged with a lethal dose of ZIKV-PR209 strain; none of the mice receiving baseline serum survived the challenge. Survival was independent of the neutralization titer., Conclusions: In this phase 1, open-label clinical trial, a DNA vaccine elicited anti-ZIKV immune responses. Further studies are needed to better evaluate the safety and efficacy of the vaccine. (Funded by GeneOne Life Science and others; ZIKA-001 ClinicalTrials.gov number, NCT02809443.)., (Copyright © 2017 Massachusetts Medical Society.)

Background: Many people living with HIV have persistent monocyte activation despite viral suppression by antiretroviral therapy (ART), which contributes to non-AIDS complications including neurocognitive and other disorders. Statins have immunomodulatory properties that might be beneficial by reducing monocyte activation., Methods: We previously characterized monocyte gene expression and inflammatory markers in 11 HIV-positive individuals on long-term ART (HIV/ART) at risk for non-AIDS complications because of low nadir CD4+ counts (median 129 cells/uL) and elevated hsCRP. Here, these individuals participated in a double-blind, randomized, placebo-controlled crossover study of 12 weeks of atorvastatin treatment. Monocyte surface markers were assessed by flow cytometry, plasma mediators by ELISA and Luminex, and monocyte gene expression by microarray analysis., Results: Among primary outcome measures, 12 weeks of atorvastatin treatment led to an unexpected increase in CCR2+ monocytes ( P =0.04), but did not affect CD16+ or CD163+ monocytes, nor levels in plasma of CCL2/MCP-1 or sCD14. Among secondary outcomes, atorvastatin treatment was associated with decreased plasma hsCRP ( P =0.035) and IL-2R ( P =0.012). Treatment was also associated with increased total CD14+ monocytes ( P =0.015), and increased plasma CXCL9 ( P =0.003) and IL-12 ( P <0.001). Comparable results were seen in a subgroup that had inflammatory marker elevations at baseline. Atorvastatin treatment did not significantly alter monocyte gene expression or normalize aberrant baseline transcriptional patterns., Conclusions: In this study of aviremic HIV+ individuals at high risk of non-AIDS events, 12 weeks of atorvastatin did not normalize monocyte gene expression patterns nor lead to significant changes in monocyte surface markers or plasma mediators linked to non-AIDS comorbidities., Competing Interests: The authors declare no competing financial or other conflicts of interest., (Copyright © Pathogens and Immunity 2021.)

The development of the National Institutes of Health (NIH) COVID-19 Treatment Guidelines began in March 2020 in response to a request from the White House Coronavirus Task Force. Within 4 days of the request, the NIH COVID-19 Treatment Guidelines Panel was established and the first meeting took place (virtually-as did subsequent meetings). The Panel comprises 57 individuals representing 6 governmental agencies, 11 professional societies, and 33 medical centers, plus 2 community members, who have worked together to create and frequently update the guidelines on the basis of evidence from the most recent clinical studies available. The initial version of the guidelines was completed within 2 weeks and posted online on 21 April 2020. Initially, sparse evidence was available to guide COVID-19 treatment recommendations. However, treatment data rapidly accrued based on results from clinical studies that used various study designs and evaluated different therapeutic agents and approaches. Data have continued to evolve at a rapid pace, leading to 24 revisions and updates of the guidelines in the first year. This process has provided important lessons for responding to an unprecedented public health emergency: Providers and stakeholders are eager to access credible, current treatment guidelines; governmental agencies, professional societies, and health care leaders can work together effectively and expeditiously; panelists from various disciplines, including biostatistics, are important for quickly developing well-informed recommendations; well-powered randomized clinical trials continue to provide the most compelling evidence to guide treatment recommendations; treatment recommendations need to be developed in a confidential setting free from external pressures; development of a user-friendly, web-based format for communicating with health care providers requires substantial administrative support; and frequent updates are necessary as clinical evidence rapidly emerges.

The potential of immunotherapy strategies utilizing broadly neutralizing antibodies (BNAbs), such as 3BNC117 and 10-1074, to limit viral replication while also facilitating clearance of HIV infected cells has heightened interest in identifying the predominant NK effector subset(s) capable of mediating antibody dependent cellular cytotoxicity (ADCC). Utilizing advanced polychromatic flow cytometry, we identified that CD57 positive NK cells from ART-suppressed in People Living With HIV (PLWH) expressed significantly higher levels of the CD16 FcγR receptor, 2B4 ADCC coreceptor, and HLA-DR activation marker while NKG2C positive NK cells expressed significantly higher levels of the CD2 ADCC coreceptor (p < 0.001, n = 32). Functionally, CD57 positive NK cells from ART-suppressed PLWH with either high or low NKG2C expansion exhibited significantly enhanced degranulation and IFN-γ production against heterologous gp120-coated ADCC targets coated with HIV reference plasma compared to CD57 negative NK cells (p = 0.0029, n = 11). CD57 positive NK cells from control donors lacking NKG2C expansion also exhibited significantly more degranulation and IFN-γ production at every timepoint tested against both heterologous ADCC targets (p = 0.019, n = 9) and HIV-1 infected autologous CD4 + primary T cells coated with BNAbs. Together, our data support CD57 positive and NKG2C positive NK cells as the predominant ADCC effector subsets capable of targeting HIV-infected CD4 + cells in the presence of 3BNC117 and 10-1074 immunotherapy., (© 2021 Wiley-VCH GmbH.)

Non-invasive biomarkers that predict HIV remission after antiretroviral therapy (ART) interruption are urgently needed. Such biomarkers can improve the safety of analytic treatment interruption (ATI) and provide mechanistic insights into the host pathways involved in post-ART HIV control. Here we report plasma glycomic and metabolic signatures of time-to-viral-rebound and probability-of-viral-remission using samples from two independent cohorts. These samples include a large number of post-treatment controllers, a rare population demonstrating sustained virologic suppression after ART-cessation. These signatures remain significant after adjusting for key demographic and clinical confounders. We also report mechanistic links between some of these biomarkers and HIV latency reactivation and/or myeloid inflammation in vitro. Finally, machine learning algorithms, based on selected sets of these biomarkers, predict time-to-viral-rebound with 74% capacity and probability-of-viral-remission with 97.5% capacity. In summary, we report non-invasive plasma biomarkers, with potential functional significance, that predict both the duration and probability of HIV remission after treatment interruption.

In the pilot NCT01935089 trial, we tested whether pegylated interferon alpha2b (Peg-IFN-α2b) with antiretroviral therapy (ART) was safe and could impact HIV and immune measures in blood and in gut-associated lymphoid tissue (GALT). Twenty HIV-1 + ART-suppressed individuals received 1 μg/kg/week Peg-IFN-α2b with ART for 20 weeks, with intermediate 4-week analytical ART interruption (ATI). Safety, immune activation, HIV viral load and integrated HIV DNA in blood, and HIV RNA and DNA in gut biopsies were measured. A total of 7/20 participants experienced grade 3-4 adverse events, while 17/20 participants completed the study. Of the 17 participants who completed the study, 8 remained suppressed during ATI, while all 17 were suppressed at end of treatment (EoT). As expected, treatment increased activation of T and natural killer (NK) cells and IFN-stimulated molecule expression on monocytes in periphery. While circulating CD4 + T cells showed a trend for a decrease in integrated HIV DNA, GALT showed a significant decrease in HIV-1 RNA + cells as measured by in situ hybridization along with a reduction in total HIV DNA and cell-associated RNA by EoT. The observed decrease in HIV-1 RNA + cells in GALT was positively associated with the decrease in activated NK cells and macrophages. This study documents for the first time that 20 weeks of immunotherapy with Peg-IFN-α2b+ART (inclusive of a 4-week ATI) is safe and results in an increase in blood and GALT immune activation and in a significant decrease in HIV-1 RNA + cells in GALT in association with changes in innate cell activation.

BackgroundWe conducted a phase I clinical trial that infused CCR5 gene-edited CD4+ T cells to determine how these T cells can better enable HIV cure strategies.MethodsThe aim of trial was to develop RNA-based approaches to deliver zinc finger nuclease (ZFN), evaluate the effect of CCR5 gene-edited CD4+ T cells on the HIV-specific T cell response, test the ability of infused CCR5 gene-edited T cells to delay viral rebound during analytical treatment interruption, and determine whether individuals heterozygous for CCR5 Δ32 preferentially benefit. We enrolled 14 individuals living with HIV whose viral load was well controlled by antiretroviral therapy (ART). We measured the time to viral rebound after ART withdrawal, the persistence of CCR5-edited CD4+ T cells, and whether infusion of 10 billion CCR5-edited CD4+ T cells augmented the HIV-specific immune response.ResultsInfusion of the CD4+ T cells was well tolerated, with no serious adverse events. We observed a modest delay in the time to viral rebound relative to historical controls; however, 3 of the 14 individuals, 2 of whom were heterozygous for CCR5 Δ32, showed post-viral rebound control of viremia, before ultimately losing control of viral replication. Interestingly, only these individuals had substantial restoration of HIV-specific CD8+ T cell responses. We observed immune escape for 1 of these reinvigorated responses at viral recrudescence, illustrating a direct link between viral control and enhanced CD8+ T cell responses.ConclusionThese findings demonstrate how CCR5 gene-edited CD4+ T cell infusion could aid HIV cure strategies by augmenting preexisting HIV-specific immune responses.REGISTRATIONClinicalTrials.gov NCT02388594.FundingNIH funding (R01AI104400, UM1AI126620, U19AI149680, T32AI007632) was provided by the National Institute of Allergy and Infectious Diseases (NIAID), the National Institute on Drug Abuse (NIDA), the National Institute of Mental Health (NIMH), and the National Institute of Neurological Disorders and Stroke (NINDS). Sangamo Therapeutics also provided funding for these studies.

Accurate characterization of the human immunodeficiency virus (HIV) reservoir is imperative to develop an effective cure. HIV was measured in antiretroviral therapy-suppressed individuals using the intact proviral DNA assay (IPDA), along with assays for total or integrated HIV DNA, and inducible HIV RNA or p24. Intact provirus correlated with total and integrated HIV., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: A vaccine against SARS-CoV-2 is of high urgency. Here the safety and immunogenicity induced by a DNA vaccine (INO-4800) targeting the full length spike antigen of SARS-CoV-2 are described., Methods: INO-4800 was evaluated in two groups of 20 participants, receiving either 1.0 mg or 2.0 mg of vaccine intradermally followed by CELLECTRA® EP at 0 and 4 weeks. Thirty-nine subjects completed both doses; one subject in the 2.0 mg group discontinued trial participation prior to receiving the second dose. ClinicalTrials.gov identifier: NCT04336410., Findings: The median age was 34.5, 55% (22/40) were men and 82.5% (33/40) white. Through week 8, only 6 related Grade 1 adverse events in 5 subjects were observed. None of these increased in frequency with the second administration. No serious adverse events were reported. All 38 subjects evaluable for immunogenicity had cellular and/or humoral immune responses following the second dose of INO-4800. By week 6, 95% (36/38) of the participants seroconverted based on their responses by generating binding (ELISA) and/or neutralizing antibodies (PRNT IC 50 ), with responder geometric mean binding antibody titers of 655.5 [95% CI (255.6, 1681.0)] and 994.2 [95% CI (395.3, 2500.3)] in the 1.0 mg and 2.0 mg groups, respectively. For neutralizing antibody, 78% (14/18) and 84% (16/19) generated a response with corresponding geometric mean titers of 102.3 [95% CI (37.4, 280.3)] and 63.5 [95% CI (39.6, 101.8)], in the respective groups. By week 8, 74% (14/19) and 100% (19/19) of subjects generated T cell responses by IFN-ɣ ELISpot assay with the median SFU per 10 6 PBMC of 46 [95% CI (21.1, 142.2)] and 71 [95% CI (32.2, 194.4)] in the 1.0 mg and 2.0 mg groups, respectively. Flow cytometry demonstrated a T cell response, dominated by CD8 + T cells co-producing IFN-ɣ and TNF-α, without increase in IL-4., Interpretation: INO-4800 demonstrated excellent safety and tolerability and was immunogenic in 100% (38/38) of the vaccinated subjects by eliciting either or both humoral or cellular immune responses., Funding: Coalition for Epidemic Preparedness Innovations (CEPI)., Competing Interests: SY, JDB, ACQ, VMA, MPM, KK, JA, AS, JP, EG, IM, PP, KS, TRFS, SR, TMcM, MD, EB, MPM, JL, MD, ASB, JES, JJK, KEB and LMH report grants from Coalition for Epidemic Preparedness Innovations, during the conduct of the study; other from Inovio Pharmaceuticals, outside the submitted work. PT, ELR, AP, MP, FIZ, KYK, YD, DF, KB, MWC, JE and DBW report grants from Coalition for Epidemic Preparedness Innovations, during the conduct of the study., (Crown Copyright © 2020 Published by Elsevier Ltd.)