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There is an unmet need for COVID-19 prevention in patient populations who have not mounted or are not expected to mount an adequate immune response to complete COVID-19 vaccination. We previously reported that a single subcutaneous 1200 mg dose of the monoclonal antibody combination casirivimab and imdevimab (CAS + IMD) prevented symptomatic SARS-CoV-2 infections by 81·4% in generally healthy household contacts of SARS-CoV-2-infected individuals over a 1-month efficacy assessment period. Here we present additional results, including the 7-month follow-up period (months 2-8), providing additional insights about the potential for efficacy in pre-exposure prophylaxis settings.This was a randomised, double-blind, placebo-controlled trial done in the USA, Romania, and Moldova in 2020-2021, before the emergence of omicron (B.1.1.529) and omicron-lineage variants. Uninfected and unvaccinated household contacts of infected individuals, judged by the investigator to be in good health, were randomly assigned (1:1) to receive 1200 mg CAS + IMD or placebo by subcutaneous injection according to a central randomisation scheme provided by an interactive web response system; randomisation was stratified per site by the test results of a local diagnostic assay for SARS-CoV-2 and age group at baseline. COVID-19 vaccines were prohibited before randomisation, but participants were allowed to receive COVID-19 vaccination during the follow-up period. Participants who developed COVID-19 symptoms during the follow-up period underwent RT-PCR testing. Prespecified endpoints included the proportion of previously uninfected and baseline-seronegative participants (seronegative-modified full analysis set) who had RT-PCR-confirmed COVID-19 in the follow-up period (post-hoc for the timepoints of months 2-5 and 6-8 only) and underwent seroconversion (ie, became seropositive, considered a proxy for any SARS-CoV-2 infections [symptomatic and asymptomatic]; prespecified up to day 57, post-hoc for all timepoints thereafter). We also assessed the incidence of treatment-emergent adverse events. This study is registered with ClinicalTrials.gov, NCT04452318.From July 13, 2020, to Oct 4, 2021, 2317 participants who were RT-PCR-negative for SARS-CoV-2 were randomly assigned, of whom 1683 (841 assigned to CAS + IMD and 842 assigned to placebo) were seronegative at baseline. During the entirety of the 8-month study, CAS + IMD reduced the risk of COVID-19 by 81·2% (nominal plt;0·0001) versus placebo (prespecified analysis). During the 7-month follow-up period, protection was greatest during months 2-5, with a 100% relative risk reduction in COVID-19 (nominal plt;0·0001; post-hoc analysis). Efficacy waned during months 6-8 (post-hoc analysis). Seroconversion occurred in 38 (4·5%) of 841 participants in the CAS + IMD group and in 181 (21·5%) of 842 in the placebo group during the 8-month study (79·0% relative risk reduction vs placebo; nominal plt;0·0001). Six participants in the placebo group were hospitalised due to COVID-19 versus none who received CAS + IMD. Serious treatment-emergent adverse events (including COVID-19) were reported in 24 (1·7%) of 1439 participants receiving CAS + IMD and in 23 (1·6%) of 1428 receiving placebo. Five deaths were reported, none of which were due to COVID-19 or related to the study drugs.CAS + IMD is not authorised in any US region as of Jan 24, 2022, because data show that CAS + IMD is not active against omicron-lineage variants. In this study, done before the emergence of omicron-lineage variants, a single subcutaneous 1200 mg dose of CAS + IMD protected against COVID-19 for up to 5 months of community exposure to susceptible strains of SARS-CoV-2 in the pre-exposure prophylaxis setting, in addition to the post-exposure prophylaxis setting that was previously shown.Regeneron Pharmaceuticals, F Hoffmann-La Roche, US National Institute of Allergy and Infectious Diseases, US National Institutes of Health.

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.

HIV-specific T cells are necessary for control of HIV-1 replication but are largely insufficient for viral clearance. This is due in part to these cells’ recognition of immunodominant but variable regions of the virus, which facilitates viral escape via mutations that do not incur viral fitness costs. HIV-specific T cells targeting conserved viral elements are associated with viral control but are relatively infrequent in people living with HIV (PLWH). The goal of this study was to increase the number of these cells via an ex vivo cell manufacturing approach derived from our clinically-validated HIV-specific expanded T-cell (HXTC) process. Using a nonhuman primate (NHP) model of HIV infection, we sought to determine i) the feasibility of manufacturing ex vivo-expanded virus-specific T cells targeting viral conserved elements (CE, CE-XTCs), ii) the in vivo safety of these products, and iii) the impact of simian/human immunodeficiency virus (SHIV) challenge on their expansion, activity, and function. NHP CE-XTCs expanded up to 10-fold following co-culture with the combination of primary dendritic cells (DCs), PHA blasts pulsed with CE peptides, irradiated GM-K562 feeder cells, and autologous T cells from CE-vaccinated NHP. The resulting CE-XTC products contained high frequencies of CE-specific, polyfunctional T cells. However, consistent with prior studies with human HXTC and these cells’ predominant CD8+ effector phenotype, we did not observe significant differences in CE-XTC persistence or SHIV acquisition in two CE-XTC-infused NHP compared to two control NHP. These data support the safety and feasibility of our approach and underscore the need for continued development of CE-XTC and similar cell-based strategies to redirect and increase the potency of cellular virus-specific adaptive immune responses.

Despite the success of antiretroviral therapy (ART) for people living with HIV, lifelong treatment is required and there is no cure. HIV can integrate in the host genome and persist for the life span of the infected cell. These latently infected cells are not recognized as foreign because they are largely transcriptionally silent, but contain replication-competent virus that drives resurgence of the infection once ART is stopped. With a combination of immune activators, neutralizing antibodies, and therapeutic vaccines, some nonhuman primate models have been cured, providing optimism for these approaches now being evaluated in human clinical trials. In vivo delivery of gene-editing tools to either target the virus, boost immunity or protect cells from infection, also holds promise for future HIV cure strategies. In this Review, we discuss advances related to HIV cure in the last 5 years, highlight remaining knowledge gaps and identify priority areas for research for the next 5 years. An effective and scalable cure strategy is a top priority for the HIV research field; this Review discusses recent advances, knowledge gaps, and priority research areas for the next 5 years.

Transmitted/founder (TF) simian-human immunodeficiency viruses (SHIVs) express HIV-1 envelopes modified at position 375 to efficiently infect rhesus macaques while preserving authentic HIV-1 Env biology. TF SHIV.C.CH505 is an extensively characterized virus shown to recapitulate key features of HIV-1 immunobiology, including CCR5-tropism, a tier 2 neutralization profile, reproducible early viral kinetics, and authentic immune responses. SHIV.C.CH505 is used frequently in nonhuman primate studies of HIV, but viral loads after months of infection are variable and typically lower than those in people living with HIV. We hypothesized that additional mutations besides Δ375 might further enhance virus fitness without compromising essential components of CH505 Env biology. From sequence analysis of SHIV.C.CH505-infected macaques across multiple experiments, we identified a signature of envelope mutations associated with higher viremia. We then used short-termin vivomutational selection and competition to identify a minimally adapted SHIV.C.CH505 with just five amino acid changes that substantially improve virus replication fitness in macaques. Next, we validated the performance of the adapted SHIVin vitroandin vivoand identified the mechanistic contributions of selected mutations.In vitro, the adapted SHIV shows improved virus entry, enhanced replication on primary rhesus cells, and preserved neutralization profiles.In vivo, the minimally adapted virus rapidly outcompetes the parental SHIV with an estimated growth advantage of 0.14 days-1and persists through suppressive antiretroviral therapy to rebound at treatment interruption. Here, we report the successful generation of a well-characterized, minimally adapted virus, termed SHIV.C.CH505.v2, with enhanced replication fitness and preserved native Env properties that can serve as a new reagent for NHP studies of HIV-1 transmission, pathogenesis, and cure.Author SummaryThe power of the nonhuman primate model of HIV to predict outcomes in people living with HIV (PLWH) depends on authentic virus-host interactions. In pursuit of viruses that generate infection that mirrors the effects of HIV-1 in PLWH, we developed a minimally adapted version of a commonly used virus, SHIV.C.CH505, which has better fitness than the parental virus while retaining important biological properties. First, we studied virus sequences from SHIV.C.CH505-infected rhesus macaques to identify a signature of mutations common to animals with higher viral loads. We then tested viruses containing the various mutations in the lab and in animals to determine the most fit version and to identify the contribution of each mutation. Ultimately, we identified a minimally adapted version of SHIV.C.CH505 with just 5 amino acid substitutions that enhances virus replication and preserves CH505 envelope properties, including sensitivity to clinically relevant broadly neutralizing antibodies. This new virus, called SHIV.C.CH505.v2 replicates well in macaques over time and persists through antiretroviral therapy. SHIV.C.CH505.v2 could be an important component of nonhuman primate studies of HIV prevention, therapy, and cure.

In untreated HIV-1 infection, rapid viral evolution allows escape from immune responses. Viral replication can be blocked by antiretroviral therapy. However, HIV-1 persists in a latent reservoir in resting CD4(+) T cells, and rebound viremia occurs following treatment interruption. The reservoir, which is maintained in part by clonal expansion, can be measured using quantitative viral outgrowth assays (QVOAs) in which latency is reversed with T cell activation to allow viral outgrowth. Recent studies have shown that viruses detected in QVOAs prior to treatment interruption often differ from rebound viruses. We hypothesized that autologous neutralizing antibodies directed at the HIV-1 envelope (Env) protein might block outgrowth of some reservoir viruses. We modified the QVOA to reflect pressure from low concentrations of autologous antibodies and showed that outgrowth of a substantial but variable fraction of reservoir viruses is blocked by autologous contemporaneous immunoglobulin G (IgG). A reduction in outgrowth of >80% was seen in 6 of 15 individuals. This effect was due to direct neutralization. We established a phylogenetic relationship between rebound viruses and viruses growing out in vitro in the presence of autologous antibodies. Some large infected cell clones detected by QVOA carried neutralization-sensitive viruses, providing a cogent explanation for differences between rebound virus and viruses detected in standard QVOAs. Measurement of the frequency of reservoir viruses capable of outgrowth in the presence of autologous IgG might allow more accurate prediction of time to viral rebound. Ultimately, therapeutic immunization targeting the subset of variants resistant to autologous IgG might contribute to a functional cure.

The primary human immunodeficiency virus (HIV) reservoir is composed of resting memory CD4+ T cells, which often express the immune checkpoint receptors programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4), which limit T cell activation via synergistic mechanisms. Using simian immunodeficiency virus (SIV)-infected, long-term antiretroviral therapy (ART)-treated rhesus macaques, we demonstrate that PD-1, CTLA-4 and dual CTLA-4/PD-1 immune checkpoint blockade using monoclonal antibodies is well tolerated, with evidence of bioactivity in blood and lymph nodes. Dual blockade was remarkably more effective than PD-1 blockade alone in enhancing T cell cycling and differentiation, expanding effector-memory T cells and inducing robust viral reactivation in plasma and peripheral blood mononuclear cells. In lymph nodes, dual CTLA-4/PD-1 blockade, but not PD-1 alone, decreased the total and intact SIV-DNA in CD4+ T cells, and SIV-DNA and SIV-RNA in B cell follicles, a major site of viral persistence during ART. None of the tested interventions enhanced SIV-specific CD8+ T cell responses during ART or viral control after ART interruption. Thus, despite CTLA-4/PD-1 blockade inducing robust latency reversal and reducing total levels of integrated virus, the degree of reservoir clearance was still insufficient to achieve viral control. These results suggest that immune checkpoint blockade regimens targeting PD-1 and/or CTLA-4, if performed in people living with HIV with sustained aviremia, are unlikely to induce HIV remission in the absence of additional interventions.

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.

SummaryCOVID-19 convalescent plasma (CCP), a passive polyclonal antibody therapeutic, has exhibited mixed results in the treatment of COVID-19. Given that the therapeutic effect of CCP may extend beyond the ability of SARS-CoV-2-specific antibody binding and neutralization to influence the evolution of the endogenous antibody response, we took a systematic and comprehensive approach to analyze SARS-CoV-2 functional antibody profiles of participants in a randomized controlled trial of CCP treatment of individuals hospitalized with COVID-19 pneumonia where CCP was associated with both decreased mortality and improved clinical severity. Using systems serology, we found that the clinical benefit of CCP is related to a shift towards reduced inflammatory Spike (S) responses and enhanced Nucleocapsid (N) humoral responses. We found CCP had the greatest clinical benefit in participants with low pre-existing anti-SARS-CoV-2 antibody function, rather than S or N antibody levels or participant demographic features. Further, CCP induced immunomodulatory changes to recipient humoral profiles persisted for at least two months, marked by the selective evolution of anti-inflammatory Fc-glycan profiles and persistently expanded nucleocapsid-specific humoral immunity following CCP therapy. Together, our findings identify a novel mechanism of action of CCP, suggest optimal patient characteristics for CCP treatment, identify long-last immunomodulatory effects of CCP, and provide guidance for development of novel N-focused antibody therapeutics for severe COVID-19 hyperinflammation.

Although several therapeutics are used to treat coronavirus disease 2019 (COVID-19) patients, there is still no definitive metabolic marker to evaluate disease severity and recovery or a quantitative test to end quarantine. Because severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infects human cells via the angiotensin-converting-enzyme 2 (ACE2) receptor and COVID-19 is associated with renin-angiotensin system dysregulation, we evaluated soluble ACE2 (sACE2) activity in the plasma/saliva of 80 hospitalized COVID-19 patients and 27 non-COVID-19 volunteers, and levels of ACE2/Ang (1-7) in plasma or membrane (mACE2) in lung autopsy samples. sACE2 activity was markedly reduced (p 0.0001) in COVID-19 plasma (n = 59) compared with controls (n = 27). Nadir sACE2 activity in early hospitalization was restored during disease recovery, irrespective of patient age, demographic variations, or comorbidity; in convalescent plasma-administered patients (n = 45), restoration was statistically higher than matched controls (n = 22, p = 0.0021). ACE2 activity was also substantially reduced in the saliva of COVID-19 patients compared with controls (p = 0.0065). There is a strong inverse correlation between sACE2 concentration and sACE2 activity and Ang (1-7) levels in participant plasmas. However, there were no difference in membrane ACE2 levels in lungs of autopsy tissues of COVID-19 (n = 800) versus other conditions (n = 300). These clinical observations suggest sACE2 activity as a potential biomarker and therapeutic target for COVID-19.

Understanding viral rebound in pediatric HIV-1 infection may inform the development of alternatives to lifelong antiretroviral therapy (ART) to achieve viral remission. We thus investigated viral rebound after analytical treatment interruption (ATI) in 10 infant macaques orally infected with SHIV.C.CH505 and treated with long-term ART. Rebound viremia was detected within 7 to 35 days of ATI in 9 of 10 animals, with posttreatment control of viremia seen in 5 of 5 Mamu-A*01+ macaques. Single-genome sequencing revealed that initial rebound virus was similar to viral DNA present in CD4+ T cells from blood, rectum, and lymph nodes before ATI. We assessed the earliest sites of viral reactivation immediately following ATI using ImmunoPET imaging. The largest increase in signal that preceded detectable viral RNA in plasma was found in the gastrointestinal (GI) tract, a site with relatively high SHIV RNA/DNA ratios in CD4+ T cells before ATI. Thus, the GI tract may be an initial source of rebound virus, but as ATI progresses, viral reactivation in other tissues likely contributes to the composition of plasma virus. Our study provides potentially novel insight into the features of viral rebound in pediatric infection and highlights the application of a noninvasive technique to monitor areas of HIV-1 expression in children.

Transfer of convalescent plasma (CP) had been proposed early during the SARS-CoV-2 pandemic as an accessible therapy, yet trial results worldwide have been mixed, potentially due to the heterogeneous nature of CP. Here we perform deep profiling of SARS-CoV-2-specific antibody titer, Fc-receptor binding, and Fc-mediated functional assays in CP units, as well as in plasma from hospitalized COVID-19 patients before and after CP administration. The profiling results show that, although all recipients exhibit expanded SARS-CoV-2-specific humoral immune responses, CP units contain more functional antibodies than recipient plasma. Meanwhile, CP functional profiles influence the evolution of recipient humoral immunity in conjuncture with the recipient’s pre-existing SARS-CoV2-specific antibody titers: CP-derived SARS-CoV-2 nucleocapsid-specific antibody functions are associated with muted humoral immune evolution in patients with high titer anti-spike IgG. Our data thus provide insights into the unexpected impact of CP-derived functional anti-spike and anti-nucleocapsid antibodies on the evolution of SARS-CoV-2-specific response following severe infection., Convalescent plasma (CP) has been trialed as a therapy for SARS-CoV-2 symptoms, but its heterogenous nature precludes uniform outcomes. Here the authors perform deep profiling of CP, as well as plasma of CP recipients before and after transfer, to find CP-mediated, spike/nucleocapsid-focused modulations of humoral responses in the recipient.

There is growing evidence that racial and ethnic minorities bear a disproportionate burden from COVID-19. Temporal changes in the pandemic epidemiology and diversity in the clinical course require careful study to identify determinants of poor outcomes.We analyzed 6255 individuals admitted with PCR-confirmed COVID-19 to one of 5 hospitals in the University of Pennsylvania Health System between March 2020 and March 2021, using electronic health records to assess risk factors and outcomes through 8 weeks post-admission. Discharge, readmission and mortality outcomes were analyzed in a multi-state model with multivariable Cox models for each transition.Mortality varied markedly over time, with cumulative incidence (95% CI) 30 days post-admission of 19.1% (16.9, 21.3) in March-April 2020, 5.7% (4.2, 7.5) in July-October 2020 and 10.5% (9.1,12.0) in January-March 2021; 26% of deaths occurred after discharge. Average age (SD) at admission varied from 62.7 (17.6) to 54.8 (19.9) to 60.5 (18.1); mechanical ventilation use declined from 21.3% to 9-11%.Compared to Caucasian, Black race was associated with more severe disease at admission, higher rates of co-morbidities and low-income resident zip code. Between-race risk differences in mortality risk diminished in multivariable models; while admitting hospital, increasing age, admission early in the pandemic, and severe disease and low blood pressure at admission were associated with increased mortality hazard. Hispanic ethnicity was associated with fewer baseline co-morbidities and lower mortality hazard (0.57, 95% CI: 0.37, .087).Multi-state modeling allows for a unified framework to analyze multiple outcomes throughout the disease course. Morbidity and mortality for hospitalized COVID-19 patients varied over time but post-discharge mortality remained non-trivial. Black race was associated with more risk factors for morbidity and with treatment at hospitals with lower mortality. Multivariable models suggest there are not between-race differences in outcomes. Future work is needed to better understand the identified between-hospital differences in mortality.

Background REGEN-COV (previously known as REGN-COV2), a combination of the monoclonal antibodies casirivimab and imdevimab, has been shown to markedly reduce the risk of hospitalization or death among high-risk persons with coronavirus disease 2019 (Covid-19). Whether subcutaneous REGEN-COV prevents severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and subsequent Covid-19 in persons at high risk for infection because of household exposure to a person with SARS-CoV-2 infection is unknown. Methods We randomly assigned, in a 1:1 ratio, participants (≥12 years of age) who were enrolled within 96 hours after a household contact received a diagnosis of SARS-CoV-2 infection to receive a total dose of 1200 mg of REGEN-COV or matching placebo administered by means of subcutaneous injection. At the time of randomization, participants were stratified according to the results of the local diagnostic assay for SARS-CoV-2 and according to age. The primary efficacy end point was the development of symptomatic SARS-CoV-2 infection through day 28 in participants who did not have SARS-COV-2 infection (as measured by reverse-transcriptase–quantitative polymerase-chain-reaction assay) or previous immunity (seronegativity). Results Symptomatic SARS-CoV-2 infection developed in 11 of 753 participants in the REGEN-COV group (1.5%) and in 59 of 752 participants in the placebo group (7.8%) (relative risk reduction [1 minus the relative risk], 81.4%; P104 copies per milliliter) was shorter (0.4 weeks and 1.3 weeks, respectively). No dose-limiting toxic effects of REGEN-COV were noted. Conclusions Subcutaneous REGEN-COV prevented symptomatic Covid-19 and asymptomatic SARS-CoV-2 infection in previously uninfected household contacts of infected persons. Among the participants who became infected, REGEN-COV reduced the duration of symptomatic disease and the duration of a high viral load. (Funded by Regeneron Pharmaceuticals and others; ClinicalTrials.gov number, NCT04452318.)

ImportanceEasy-to-administer antiviral treatments may be used to prevent progression from asymptomatic infection to COVID-19 and to reduce viral carriage.ObjectiveEvaluate the efficacy and safety of subcutaneous casirivimab and imdevimab antibody combination (REGEN-COV) to prevent progression from early asymptomatic SARS-CoV-2 infection to COVID-19.DesignRandomized, double-blind, placebo-controlled, phase 3 study that enrolled asymptomatic close contacts living with a SARS-CoV-2–infected household member (index case). Participants who were SARS-CoV-2 RT-qPCR–positive at baseline were included in the analysis reported here.SettingMulticenter trial conducted at 112 sites in the United States, Romania, and Moldova.ParticipantsAsymptomatic individuals ≥12 years of age were eligible if identified within 96 hours of collection of the index case’s positive SARS-CoV-2 test sample.InterventionsA total of 314 asymptomatic, SARS-CoV-2 RT-qPCR–positive individuals living with an infected household contact were randomized 1:1 to receive a single dose of subcutaneous REGEN-COV 1200mg (n=158) or placebo (n=156).Main Outcome(s) and Measure(s)The primary endpoint was the proportion of participants who developed symptomatic COVID-19 during the 28-day efficacy assessment period. The key secondary efficacy endpoints were the number of weeks of symptomatic SARS-CoV-2 infection and the number of weeks of high viral load (>4 log10 copies/mL). Safety was assessed in all treated participants.ResultsSubcutaneous REGEN-COV 1200mg significantly prevented progression from asymptomatic to symptomatic disease compared with placebo (31.5% relative risk reduction; 29/100 [29.0%] vs 44/104 [42.3%], respectively; P=.0380). REGEN-COV reduced the overall population burden of high–viral load weeks (39.7% reduction vs placebo; 48 vs 82 total weeks; P=.0010) and of symptomatic weeks (45.3% reduction vs placebo; 89.6 vs 170.3 total weeks; P=.0273), the latter corresponding to an approximately 5.6-day reduction in symptom duration per symptomatic participant. Six placebo-treated participants had a COVID-19–related hospitalization or ER visit versus none for those receiving REGEN-COV. The proportion of participants receiving placebo who had ≥1 treatment-emergent adverse events was 48.1% compared with 33.5% for those receiving REGEN-COV, including events related (39.7% vs 25.8%, respectively) or not related (16.0% vs 11.0%, respectively) to COVID-19.Conclusions and RelevanceSubcutaneous REGEN-COV 1200mg prevented progression from asymptomatic SARS-CoV-2 infection to COVID-19, reduced the duration of high viral load and symptoms, and was well tolerated.Trial RegistrationClinicalTrials.gov Identifier, NCT04452318KEY POINTSQuestionCan treatment with the anti–SARS-CoV-2 antibody combination REGEN-COV prevent COVID-19 and reduce viral load when given to recently exposed and asymptomatic individuals?FindingsIn this randomized, double-blind, phase 3 trial, subcutaneously administered REGEN-COV 1200 mg significantly reduced progression of asymptomatic SARS-CoV-2 infection to symptomatic infection (ie, COVID-19) by 31.5% compared with placebo. REGEN-COV also reduced the overall population burden of high viral load weeks (39.7% reduction vs placebo; 48 vs 82 total weeks; P=.0010).MeaningIn the current pandemic, utilization of subcutaneous REGEN-COV prevents progression of early asymptomatic infection to COVID-19 and reduces viral carriage.

A March-June 2021 representative serosurvey among Sitakunda subdistrict (Chattogram, Bangladesh) residents found an adjusted prevalence of severe acute respiratory syndrome coronavirus 2 antibodies of 64.1% (95% credible interval 60.0%-68.1%). Before the Delta variant surge, most residents had been infected, although cumulative confirmed coronavirus disease incidence was low.

The development of a maternal HIV vaccine to synergize with current antiretroviral drug prophylaxis can overcome implementation challenges and further reduce mother-to-child transmission (MTCT) of HIV. Both the epitope-specificity and autologous neutralization capacity of maternal HIV envelope (Env)-specific antibodies have been implicated in decreased risk of MTCT of HIV. Our goal was to determine if heterologous HIV Env immunization of SHIV.C.CH505-infected, ART-suppressed female rhesus macaques (RMs) could boost autologous Env-specific antibodies. SHIV.C.CH505-infected female RMs (n = 12), began a daily ART regimen at 12 weeks post-infection (wpi), which was continued for 12 weeks. Starting 2 weeks after ART initiation, RMs received 3 monthly immunizations with HIV b.63521/1086.C gp120 or placebo (n = 6/group) vaccine with adjuvant STR8S-C. Compared to the placebo-immunized animals, Env-vaccinated, SHIV-infected RMs exhibited enhanced IgG binding, avidity, and ADCC responses against the vaccine immunogens and the autologous SHIV.C.CH505 Env. Notably, the Env-specific memory B cells elicited by heterologous vaccination were dominated by cells that recognized the SHIV.C.CH505 Env, the antigen of primary exposure. Thus, vaccination of SHIV-infected, ART-suppressed RMs with heterologous HIV Envs can augment multiple components of the antibody response against the Env antigen of primary exposure, suggesting antigenic seniority. Our results suggest that a universal maternal HIV vaccination regimen can be developed to leverage antigenic seniority in targeting the maternal autologous virus pool.

SHIVs have been extensively used in a nonhuman primate (NHP) model for HIV research. In this study, we investigated viral reservoirs in tissues and immune responses in an NHP model inoculated with newly generated transmitted/founder HIV-1 clade C-based SHIV.C.CH848., Chimeric simian/human immunodeficiency viruses (SHIVs) are widely used in nonhuman primate models to recapitulate human immunodeficiency virus (HIV) infection in humans, yet most SHIVs fail to establish persistent viral infection. We investigated immunological and virological events in rhesus macaques infected with the newly developed SHIV.C.CH848 (SHIVC) and treated with combined antiretroviral therapy (cART). Similar to HIV/simian immunodeficiency virus (SIV) infection, SHIV.C.CH848 infection established viral reservoirs in CD4+ T cells and myeloid cells, accompanied by productive infection and depletion of CD4+ T cells in systemic and lymphoid tissues throughout SHIV infection. Despite 6 months of cART-suppressed viral replication, integrated proviral DNA levels remained stable, especially in CD4+ T cells, and the viral rebound was also observed after ART interruption. Autologous neutralizing antibodies to the parental HIV-1 strain CH848 were detected, with limited viral evolution at 5 months postinfection. In comparison, heterogenous neutralizing antibodies in SHIV.C.CH848-infected macaques were not detected except for 1 (1 of 10) animal at 2 years postinfection. These findings suggest that SHIV.C.CH848, a novel class of transmitted/founder SHIVs, can establish sustained viremia and viral reservoirs in rhesus macaques with clinical immunodeficiency consequences, providing a valuable SHIV model for HIV research. IMPORTANCE SHIVs have been extensively used in a nonhuman primate (NHP) model for HIV research. In this study, we investigated viral reservoirs in tissues and immune responses in an NHP model inoculated with newly generated transmitted/founder HIV-1 clade C-based SHIV.C.CH848. The data show that transmitted founder (T/F) SHIVC infection of macaques more closely recapitulates the virological and clinical features of HIV infection, including persistent viremia and viral rebound once antiretroviral therapy is discontinued. These results suggest this CCR5-tropic, SHIVC strain is valuable for testing responses to HIV vaccines and therapeutics.

In the absence of an effective vaccine or monoclonal therapeutic, transfer of convalescent plasma (CCP) was proposed early in the SARS-CoV-2 pandemic as an easily accessible therapy. However, despite the global excitement around this historically valuable therapeutic approach, results from CCP trials have been mixed and highly debated. Unlike other therapeutic interventions, CCP represents a heterogeneous drug. Each CCP unit is unique and collected from an individual recovered COVID-19 patient, making the interpretation of therapeutic benefit more complicated. While the prevailing view in the field would suggest that it is administration of neutralizing antibodies via CCP that centrally provides therapeutic benefit to newly infected COVID-19 patients, many hospitalized COVID-19 patients already possess neutralizing antibodies. Importantly, the therapeutic benefit of antibodies can extend far beyond their simple ability to bind and block infection, especially related to their ability to interact with the innate immune system. In our work we deeply profiled the SARS-CoV-2-specific Fc-response in CCP donors, along with the recipients prior to and after CCP transfer, revealing striking SARS-CoV-2 specific Fc-heterogeneity across CCP units and their recipients. However, CCP units possessed more functional antibodies than acute COVID-19 patients, that shaped the evolution of COVID-19 patient humoral profiles via distinct immunomodulatory effects that varied by pre-existing SARS-CoV-2 Spike (S)-specific IgG titers in the patients. Our analysis identified surprising influence of both S and Nucleocapsid (N) specific antibody functions not only in direct antiviral activity but also in anti-inflammatory effects. These findings offer insights for more comprehensive interpretation of correlates of immunity in ongoing large scale CCP trials and for the design of next generation therapeutic design.

SHIV infection of Indian rhesus macaques is an important animal model for studying HIV-1 transmission, prevention, immunopathogenesis, and cure. Such research is timely, given recent progress with active and passive immunization and novel approaches to HIV-1 cure., Previously, we showed that substitution of HIV-1 envelope (Env) residue 375-Ser by bulky aromatic residues enhances binding to rhesus CD4 and enables primary HIV-1 Envs to support efficient replication as simian-human immunodeficiency virus (SHIV) chimeras in rhesus macaques (RMs). Here, we test this design strategy more broadly by constructing SHIVs containing 10 primary Envs corresponding to HIV-1 subtypes A, B, C, AE, and AG. All 10 SHIVs bearing wild-type Env375 residues replicated efficiently in human CD4+ T cells, but only one replicated efficiently in primary rhesus cells. This was a subtype AE SHIV that naturally contained His at Env375. Replacement of wild-type Env375 residues by Trp, Tyr, Phe, or His in the other nine SHIVs led to efficient replication in rhesus CD4+ T cells in vitro and in vivo. Nine SHIVs containing optimized Env375 alleles were grown large-scale in primary rhesus CD4+ T cells to serve as challenge stocks in preclinical prevention trials. These virus stocks were genetically homogeneous, native-like in Env antigenicity and tier 2 neutralization sensitivity, and transmissible by rectal, vaginal, penile, oral, or intravenous routes. To facilitate future SHIV constructions, we engineered a simplified second-generation design scheme and validated it in RMs. Overall, our findings demonstrate that SHIVs bearing primary Envs with bulky aromatic substitutions at Env375 consistently replicate in RMs, recapitulating many features of HIV-1 infection in humans. Such SHIVs are efficiently transmitted by mucosal routes common to HIV-1 infection and can be used to test vaccine efficacy in preclinical monkey trials. IMPORTANCE SHIV infection of Indian rhesus macaques is an important animal model for studying HIV-1 transmission, prevention, immunopathogenesis, and cure. Such research is timely, given recent progress with active and passive immunization and novel approaches to HIV-1 cure. Given the multifaceted roles of HIV-1 Env in cell tropism and virus entry, and as a target for neutralizing and nonneutralizing antibodies, Envs selected for SHIV construction are of paramount importance. Until recently, it has been impossible to strategically design SHIVs bearing clinically relevant Envs that replicate consistently in monkeys. This changed with the discovery that bulky aromatic substitutions at residue Env375 confer enhanced affinity to rhesus CD4. Here, we show that 10 new SHIVs bearing primary HIV-1 Envs with residue 375 substitutions replicated efficiently in RMs and could be transmitted efficiently across rectal, vaginal, penile, and oral mucosa. These findings suggest an expanded role for SHIVs as a model of HIV-1 infection.

Daily burden and clinical toxicities associated with antiretroviral therapy (ART) emphasize the need for alternative strategies to induce long-term human immunodeficiency virus (HIV) remission upon ART cessation. Broadly neutralizing antibodies (bNAbs) can both neutralize free virions and mediate effector functions against infected cells and therefore represent a leading immunotherapeutic approach. To increase potency and breadth, as well as to limit the development of resistant virus strains, it is likely that bNAbs will need to be administered in combination. It is therefore critical to identify bNAb combinations that can achieve robust polyfunctional antiviral activity against a high number of HIV strains. In this study, we systematically assessed the abilities of single bNAbs and triple bNAb combinations to mediate robust polyfunctional antiviral activity against a large panel of cross-clade simian-human immunodeficiency viruses (SHIVs), which are commonly used as tools for validation of therapeutic strategies targeting the HIV envelope in nonhuman primate models. We demonstrate that most bNAbs are capable of mediating both neutralizing and nonneutralizing effector functions against cross-clade SHIVs, although the susceptibility to V3 glycan-specific bNAbs is highly strain dependent. Moreover, we observe a strong correlation between the neutralization potencies and nonneutralizing effector functions of bNAbs against the transmitted/founder SHIV CH505. Finally, we identify several triple bNAb combinations comprising of CD4 binding site-, V2-glycan-, and gp120-gp41 interface-targeting bNAbs that are capable of mediating synergistic polyfunctional antiviral activities against multiple clade A, B, C, and D SHIVs. IMPORTANCE Optimal bNAb immunotherapeutics will need to mediate multiple antiviral functions against a broad range of HIV strains. Our systematic assessment of triple bNAb combinations against SHIVs will identify bNAbs with synergistic, polyfunctional antiviral activity that will inform the selection of candidate bNAbs for optimal combination designs. The identified combinations can be validated in vivo in future passive immunization studies using the SHIV challenge model.

Type 1 interferons (IFN-I) are potent innate antiviral effectors that constrain HIV-1 transmission. However, harnessing these cytokines for HIV-1 cure strategies has been hampered by an incomplete understanding of their antiviral activities at later stages of infection. Here, we characterized the IFN-I sensitivity of 500 clonally derived HIV-1 isolates from the plasma and CD4+ T cells of 26 individuals sampled longitudinally after transmission or after antiretroviral therapy (ART) and analytical treatment interruption. We determined the concentration of IFNα2 and IFNβ that reduced viral replication in vitro by 50% (IC50) and found consistent changes in the sensitivity of HIV-1 to IFN-I inhibition both across individuals and over time. Resistance of HIV-1 isolates to IFN-I was uniformly high during acute infection, decreased in all individuals in the first year after infection, was reacquired concomitant with CD4+ T cell loss, and remained elevated in individuals with accelerated disease. HIV-1 isolates obtained by viral outgrowth during suppressive ART were relatively IFN-I sensitive, resembling viruses circulating just before ART initiation. However, viruses that rebounded after treatment interruption displayed the highest degree of IFNα2 and IFNβ resistance observed at any time during the infection course. These findings indicate a dynamic interplay between host innate responses and the evolving HIV-1 quasispecies, with the relative contribution of IFN-I to HIV-1 control affected by both ART and analytical treatment interruption. Although elevated at transmission, host innate pressures are the highest during viral rebound, limiting the viruses that successfully become reactivated from latency to those that are IFN-I resistant.

Type 1 interferons (IFN-I) are potent innate antiviral effectors that constrain HIV-1 transmission. However, harnessing these cytokines for HIV-1 cure strategies has been hampered by an incomplete understanding of their anti-viral activities at later stages of infection. Here, we characterized the IFN-I sensitivity of 500 clonally-derived HIV-1 isolates from plasma and CD4+ T cells of 26 individuals sampled longitudinally following transmission and/or after antiretroviral therapy (ART) and analytical treatment interruption (ATI). Determining the concentration of IFNα2 and IFNβ that reduced HIV-1 replication by 50% (IC50), we found remarkably consistent changes in the sensitivity of viruses to IFN-I inhibition, both across individuals and over time. IFN-I resistance was uniformly high during acute infection, decreased in all subjects in the first year post-infection, was reacquired concomitant with CD4+ T cell loss, and remained elevated in subjects with accelerated disease. Isolates obtained by viral outgrowth during suppressive ART were relatively IFN-I sensitive, resembling viruses circulating just prior to ART initiation. However, viruses that rebounded following treatment interruption displayed the highest levels of IFNα2 and IFNβ resistance observed at any time during the infection course. These findings indicate a dynamic interplay between host innate immune responses and the evolving HIV-1 quasispecies, with the relative contribution of IFN-I to HIV-1 control impacted by both ART and ATI. Although elevated at transmission, IFN-mediated pressures are the highest during viral rebound, limiting the viruses that successfully reactivate from latency.One Sentence SummaryHIV-1 resistance to IFN-I is highest during acute infection and following analytic treatment interruption, indicating a dynamic interplay between host innate immunity and virus biology.

Uncovering the sanctuaries of the long-lived HIV-1 reservoir is crucial to develop cure strategies. Pediatric immunity is distinct from that of adults, which may alter where the reservoir is established in infancy. Thus, it is important to utilize pediatric models to inform cure-directed approaches for HIV-1-infected children. We used an infant rhesus macaque model of HIV-1 infection via breastfeeding to identify key sites of viral persistence under antiretroviral therapy (ART). The gastrointestinal tract was found to be a site for low-level viral transcription during ART. We also show that naive CD4+ T cells harbored intact provirus and were a major contributor to blood and lymphoid reservoir size. This is particularly striking, as memory CD4+ T cells are generally regarded as the main source of latent HIV/simian immunodeficiency virus (SIV) infection of adult humans and rhesus macaques. Our findings highlight unique features of reservoir composition in pediatric infection that should be considered for eradication efforts., Mother-to-child transmission of human immunodeficiency virus type 1 (HIV-1) continues to cause new pediatric cases of infection through breastfeeding, a setting where it is not always possible to initiate early antiretroviral therapy (ART). Without novel interventions that do not rely on daily ART, HIV-1-infected children face lifelong medications to control infection. A detailed analysis of virus persistence following breast milk transmission of HIV-1 and ART has not been performed. Here, we used infant rhesus macaques orally infected with simian/human immunodeficiency virus (SHIV) (SHIV.C.CH505) to identify cellular and anatomical sites of virus persistence under ART. Viral DNA was detected at similar levels in blood and tissue CD4+ T cells after a year on ART, with virus in blood and lymphoid organs confirmed to be replication competent. Viral RNA/DNA ratios were elevated in rectal CD4+ T cells compared to those of other sites (P ≤ 0.0001), suggesting that the gastrointestinal tract is an active site of virus transcription during ART-mediated suppression of viremia. SHIV.C.CH505 DNA was detected in multiple CD4+ T cell subsets, including cells with a naive phenotype (CD45RA+ CCR7+ CD95–). While the frequency of naive cells harboring intact provirus was lower than in memory cells, the high abundance of naive cells in the infant CD4+ T cell pool made them a substantial source of persistent viral DNA (approximately 50% of the total CD4+ T cell reservoir), with an estimated 1:2 ratio of intact provirus to total viral DNA. This viral reservoir profile broadens our understanding of virus persistence in a relevant infant macaque model and provides insight into targets for cure-directed approaches in the pediatric population. IMPORTANCE Uncovering the sanctuaries of the long-lived HIV-1 reservoir is crucial to develop cure strategies. Pediatric immunity is distinct from that of adults, which may alter where the reservoir is established in infancy. Thus, it is important to utilize pediatric models to inform cure-directed approaches for HIV-1-infected children. We used an infant rhesus macaque model of HIV-1 infection via breastfeeding to identify key sites of viral persistence under antiretroviral therapy (ART). The gastrointestinal tract was found to be a site for low-level viral transcription during ART. We also show that naive CD4+ T cells harbored intact provirus and were a major contributor to blood and lymphoid reservoir size. This is particularly striking, as memory CD4+ T cells are generally regarded as the main source of latent HIV/simian immunodeficiency virus (SIV) infection of adult humans and rhesus macaques. Our findings highlight unique features of reservoir composition in pediatric infection that should be considered for eradication efforts.

The “shock-and-kill” human immunodeficiency virus type 1 (HIV-1) cure strategy involves latency reversal followed by immune-mediated clearance of infected cells. We have previously shown that activation of the noncanonical NF-κB pathway using an inhibitor of apoptosis (IAP), AZD5582, reverses HIV/simian immunodeficiency virus (SIV) latency. Here, we combined AZD5582 with bispecific HIVxCD3 DART molecules to determine the impact of this approach on persistence. Rhesus macaques (RMs) (n = 13) were infected with simian/human immunodeficiency virus SHIV.C.CH505.375H.dCT, and triple antiretroviral therapy (ART) was initiated after 16 weeks. After 42 weeks of ART, 8 RMs received a cocktail of 3 HIVxCD3 DART molecules having human A32, 7B2, or PGT145 anti-HIV-1 envelope (Env) specificities paired with a human anti-CD3 specificity that is rhesus cross-reactive. The remaining 5 ART-suppressed RMs served as controls. For 10 weeks, a DART molecule cocktail was administered weekly (each molecule at 1 mg/kg of body weight), followed 2 days later by AZD5582 (0.1 mg/kg). DART molecule serum concentrations were well above those considered adequate for redirected killing activity against Env-expressing target cells but began to decline after 3 to 6 weekly doses, coincident with the development of antidrug antibodies (ADAs) against each of the DART molecules. The combination of AZD5582 and the DART molecule cocktail did not increase on-ART viremia or cell-associated SHIV RNA in CD4(+) T cells and did not reduce the viral reservoir size in animals on ART. The lack of latency reversal in the model used in this study may be related to low pre-ART viral loads (median

A robust simian-human immunodeficiency virus (SHIV)-macaque model of latency is critical to investigate eradicative and suppressive strategies that target HIV-1 Env. To this end, we previously reported a novel strategy for constructing SHIVs that bear primary or transmitted/founder (TF) Envs with modifications at Env residue 375 that enable efficient replication in Indian rhesus macaques (RM). Such TF SHIVs, however, have not been examined for their suitability for HIV-1 latency and cure research. Here, we evaluate two promising TF SHIVs, SHIV.D.191859 and SHIV.C.CH848, which encode TF subtype D and C HIV-1 Envs, respectively, for their viral kinetics and persistence during suppressive combination antiretroviral therapy (cART) and treatment interruption in RM. Our results suggest that the viral kinetics of these SHIVs in RM during acute, early, and chronic infection, and upon cART initiation, maintenance and discontinuation, mirror those of HIV-1 infection. We demonstrate consistent early peak and set point viremia, rapid declines in viremia to undetectable plasma titers following cART initiation, infection of long-lived cellular subsets and establishment of viral latency, and viral rebound with return to pretreatment set point viremia following treatment interruption. The viral dynamics and reservoir biology of SHIV.D.191859, and to a lesser extent SHIV.C.CH848, during chronic infection, cART administration, and upon treatment interruption suggest that these TF SHIVs are promising reagents for a SHIV model of HIV-1 latency and cure. IMPORTANCE Simian-human immunodeficiency viruses (SHIVs) have been successfully used for over 2 decades to study virus-host interactions, transmission, and pathogenesis in rhesus macaques. The majority of Env trimers of most previously studied SHIVs, however, do not recapitulate key properties of transmitted/founder (TF) or primary HIV-1 isolates, such as CCR5 tropism, tier 2 neutralization resistance, and native trimer conformation. Here, we test two recently generated TF SHIVs, SHIV.D.191859 and SHIV.C.CH848, which were designed to address these issues as components of a nonhuman primate model of HIV-1 latency. We conclude that the TF SHIV-macaque model reflects several hallmarks of HIV and SIV infection and latency. Results suggest that this model has broad applications for evaluating eradicative and suppressive strategies against the HIV reservoir, including Env-specific interventions, therapeutic vaccines, and engineered T cells.

Therapeutic strategies are being clinically tested either to eradicate latent HIV reservoirs or to achieve virologic control in the absence of antiretroviral therapy. Attaining this goal will require a consensus on how best to measure the numbers of persistently infected cells with the potential to cause viral rebound after antiretroviral-therapy cessation in assessing the results of cure-directed strategies in vivo. Current measurements assess various aspects of the HIV provirus and its functionality and produce divergent results. Here, we provide recommendations from the BEAT-HIV Martin Delaney Collaboratory on which viral measurements should be prioritized in HIV-cure-directed clinical trials. This work was supported by the NIH-funded BEAT-HIV Martin Delaney Collaboratory to cure HIV-1 infection (1UM1Al126620). LJM is also supported by NIH R01 AI065279, U01 AI065279, R01 DA048728, R01 DA049666, Kean Family Professorship, and the Philadelphia Foundation (Roberts I. Jacobs Fund). M-AM is supported by NIH grants (DK123733, AG062383, NS117458, AI143385, AI129636, and NS106970), The Foundation for AIDS Research (amfAR) impact grant # 109840–65-RGRL, and W.W. Smith Charitable Trust grant # A1901, Wistar Cancer Center Support Grant P30 CA010815–49S2, and the Penn Center for AIDS Research (AI 045008). MJB is supported by The Miguel Servet program funded by the Spanish Health Institute Carlos III (CP17/00179). M. L. Is supported by NIH grants AI117841, AI120008, AI124776, AI130005, AI122377, and AI135940. XGY is supported by NIH grants AI116228, AI078799, HL134539, AI125109, and DA047034. RS supported by AI126603, AI126620 and AI12661, AI094189, 43222 Howard Hughes Medical Institute, and the Bill and Melinda Gates Foundation (OPP1115715). VP supported by AI143567, AI124843. Y-C Ho supported by Yale Top Scholar, Rudolf J. Anderson Fellowship, AI141009, DA047037, AI118402, W.W. Smith AIDS Research Grant, Gilead AIDS Research Grant, Gilead Research Scholar Grant, AI150464, AI094189, AI14868. J.D.E is supported by NIH and the Bill and Melinda Gates Foundation grants 75N93019C00070, AI133706, AI110164, AI141258, AI143411, AI149672, CA206466, DK119945, INV-002704, and OD011092–60, and OPPO1108533. Sí

Key Points Question What patient characteristics are associated with benefit from treatment with COVID-19 convalescent plasma (CCP)? Findings This prognostic study of 2287 patients hospitalized with COVID-19 identified a combination of baseline characteristics that predict a gradation of benefit from CCP compared with treatment without CCP. Preexisting health conditions (diabetes, cardiovascular and pulmonary diseases), blood type A or AB, and earlier stage of COVID-19 were associated with a larger treatment benefit. Meaning These findings suggest that simple patient information collected at hospitalization can be used to guide CCP treatment decisions for patients with COVID-19., This prognostic study develops an index for predicting the expected relative COVID-19 convalescent plasma treatment benefit for patients hospitalized for COVID-19 using patients’ baseline characteristics., Importance Identifying which patients with COVID-19 are likely to benefit from COVID-19 convalescent plasma (CCP) treatment may have a large public health impact. Objective To develop an index for predicting the expected relative treatment benefit from CCP compared with treatment without CCP for patients hospitalized for COVID-19 using patients’ baseline characteristics. Design, Setting, and Participants This prognostic study used data from the COMPILE study, ie, a meta-analysis of pooled individual patient data from 8 randomized clinical trials (RCTs) evaluating CCP vs control in adults hospitalized for COVID-19 who were not receiving mechanical ventilation at randomization. A combination of baseline characteristics, termed the treatment benefit index (TBI), was developed based on 2287 patients in COMPILE using a proportional odds model, with baseline characteristics selected via cross-validation. The TBI was externally validated on 4 external data sets: the Expanded Access Program (1896 participants), a study conducted under Emergency Use Authorization (210 participants), and 2 RCTs (with 80 and 309 participants). Exposure Receipt of CCP. Main Outcomes and Measures World Health Organization (WHO) 11-point ordinal COVID-19 clinical status scale and 2 derivatives of it (ie, WHO score of 7-10, indicating mechanical ventilation to death, and WHO score of 10, indicating death) at day 14 and day 28 after randomization. Day 14 WHO 11-point ordinal scale was used as the primary outcome to develop the TBI. Results A total of 2287 patients were included in the derivation cohort, with a mean (SD) age of 60.3 (15.2) years and 815 (35.6%) women. The TBI provided a continuous gradation of benefit, and, for clinical utility, it was operationalized into groups of expected large clinical benefit (B1; 629 participants in the derivation cohort [27.5%]), moderate benefit (B2; 953 [41.7%]), and potential harm or no benefit (B3; 705 [30.8%]). Patients with preexisting conditions (diabetes, cardiovascular and pulmonary diseases), with blood type A or AB, and at an early COVID-19 stage (low baseline WHO scores) were expected to benefit most, while those without preexisting conditions and at more advanced stages of COVID-19 could potentially be harmed. In the derivation cohort, odds ratios for worse outcome, where smaller odds ratios indicate larger benefit from CCP, were 0.69 (95% credible interval [CrI], 0.48-1.06) for B1, 0.82 (95% CrI, 0.61-1.11) for B2, and 1.58 (95% CrI, 1.14-2.17) for B3. Testing on 4 external datasets supported the validation of the derived TBIs. Conclusions and Relevance The findings of this study suggest that the CCP TBI is a simple tool that can quantify the relative benefit from CCP treatment for an individual patient hospitalized with COVID-19 that can be used to guide treatment recommendations. The TBI precision medicine approach could be especially helpful in a pandemic.

Purpose of review Clinical trials with an antiretroviral therapy (ART) interruption remains indispensable for assessing strategies for ART-free HIV remission. This review highlights the lessons learned from ART interruption studies so far, including the risks to the participants and implications for HIV remission. Recent findings Historically, analytic HIV treatment interruption (ATI) studies were commonly designed with a prolonged duration of ART interruption and with viral load set point as the primary outcome. For a variety of reasons, including participant risk, recent treatment interruption trials have frequently used time to viral rebound as the primary endpoint and have restarted ART once a predetermined viral load threshold is reached. Through treatment interruption trials, investigators have tested the efficacy of therapeutic and curative strategies that showed promise in preclinical trials, including therapeutic vaccines, latency-reversing agents, and broadly neutralizing antibodies. In most populations, ATI trials have been well tolerated, with few adverse clinical events and no significant changes to the reservoir. Several reservoir predictors of HIV-rebound timing have been reported, with a subset of trials uncovering posttreatment controllers who can maintain HIV remission despite ART discontinuation. Summary Treatment interruption trials are a vital tool, but their optimal design remain uncertain and must balance participant risks with scientific rigor. The ability to predict the timing or extent of HIV rebound and identify mechanisms of posttreatment control may accelerate the development of novel therapeutics for sustained HIV remission.

BACKGROUND. The effect of a brief analytical treatment interruption (ATI) on the HIV-1 latent reservoir of individuals who initiate antiretroviral therapy (ART) during chronic infection is unknown. METHODS. We evaluated the impact of transient viremia on the latent reservoir in participants who underwent an ATI and at least 6 months of subsequent viral suppression in a clinical trial testing the effect of passive infusion of the broadly neutralizing Ab VRC01 during ATI. RESULTS. Measures of total HIV-1 DNA, cell-associated RNA, and infectious units per million cells (IUPM) (measured by quantitative viral outgrowth assay [QVOA]) were not statistically different before or after ATI. Phylogenetic analyses of HIV-1 env sequences from QVOA and proviral DNA demonstrated little change in the composition of the virus populations comprising the pre- and post-ATI reservoir. Expanded clones were common in both QVOA and proviral DNA sequences. The frequency of clonal populations differed significantly between QVOA viruses, proviral DNA sequences, and the viruses that reactivated in vivo. CONCLUSIONS. The results indicate that transient viremia from ATI does not substantially alter measures of the latent reservoir, that clonal expansion is prevalent within the latent reservoir, and that characterization of latent viruses that can reactivate in vivo remains challenging. TRIAL REGISTRATION. ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT02463227","term_id":"NCT02463227"}}NCT02463227 FUNDING. Funding was provided by the NIH.

Objectives For both HIV-1 and hepatitis C virus (HCV), assessing the stringency of the transmission process is a scientific priority. Enumerations of transmitted/founder (TF) viruses have shown a strict transmission bottleneck in sexual transmission of HIV-1 and a wide range in the multiplicity of infection in HCV. Here, we aim to determine the stringency of parenteral transmission for HIV-1 and HCV in people who inject drugs (PWID). Design We used molecular sequencing and several complementary analyses to enumerate the TF HIV-1 and HCV variants in a well described cohort of PWID in Xinjiang, China. Methods We performed single genome sequencing of HIV-1 env and 5' half HCV genomes, then applied phylogenetic analysis and validated models of early virus diversification to enumerate TF viruses in 60 PWID. We used multivariate analysis to determine correlates of multivariant transmission (MVT). Results We generated 1070 env region sequences from 33 HIV-1 early infected individuals and 773 5' half region sequences from 27 HCV early infected individuals. We found rates of MVT of 39 and 54%, respectively, for HIV-1 and HCV, with a limited range in the number of TF viruses in both infections. Behavioural characteristics suggested high-risk injection practices and lower risk sexual practices; we did not find an association between any specific behaviours and MVT. Conclusion MVT is frequent in parenteral transmission of both HIV-1 and HCV in Xinjiang PWID, indicating a less stringent transmission process than sexual transmission.

Simian-human immunodeficiency viruses (SHIVs) have been utilized to test vaccine efficacy and characterize mechanisms of viral transmission and pathogenesis. However, the majority of SHIVs currently available have significant limitations in that they were developed using sequences from chronically HIV-infected individuals or uncommon HIV subtypes or were optimized for the macaque model by serially passaging the engineered virus in vitro or in vivo. Recently, a newly developed SHIV, SHIV.C.CH505.375H.dCT (SHIV.CH505), which incorporates vpu-env (gp140) sequences from a transmitted/founder HIV-1 subtype C strain, was shown to retain attributes of primary HIV-1 strains. However, a comprehensive analysis of the immunopathology that results from infection with this virus, especially in critical tissue compartments like the intestinal mucosa, has not been completed. In this study, we evaluated the viral dynamics and immunopathology of SHIV.CH505 in rhesus macaques. In line with previous findings, we found that SHIV.CH505 is capable of infecting and replicating efficiently in rhesus macaques, resulting in peripheral viral kinetics similar to that seen in pathogenic SIV and HIV infection. Furthermore, we observed significant and persistent depletions of CCR5(+) and CCR6(+) CD4(+) T cells in mucosal tissues, decreases in CD4(+) T cells producing Th17 cell-associated cytokines, CD8(+) T cell dysfunction, and alterations of B cell and innate immune cell function, indicating that SHIV.CH505 elicits intestinal immunopathology typical of SIV/HIV infection. These findings suggest that SHIV.CH505 recapitulates the early viral replication dynamics and immunopathogenesis of HIV-1 infection of humans and thus can serve as a new model for HIV-1 pathogenesis, treatment, and prevention research. IMPORTANCE The development of chimeric SHIVs has been instrumental in advancing our understanding of HIV-host interactions and allowing for in vivo testing of novel treatments. However, many of the currently available SHIVs have distinct drawbacks and are unable to fully reflect the features characteristic of primary SIV and HIV strains. Here, we utilize rhesus macaques to define the immunopathogenesis of the recently developed SHIV.CH505, which was designed without many of the limitations of previous SHIVs. We observed that infection with SHIV.CH505 leads to peripheral viral kinetics and mucosal immunopathogenesis comparable with those caused by pathogenic SIV and HIV. Overall, these data provide evidence of the value of SHIV.CH505 as an effective model of SIV/HIV infection and an important tool that can be used in future studies, including preclinical testing of new therapies or prevention strategies.

Novel interventions that do not rely on daily adherence to ART are needed to achieve sustained viral remission for perinatally infected children, who currently rely on lifelong ART. Considering the risks and expense associated with ART interruption trials, the identification of biomarkers of viral rebound will prioritize promising therapeutic intervention strategies, including anti-HIV Env protein therapeutics. However, comprehensive studies to identify those biomarkers are logistically challenging in human infants, demanding the need for relevant nonhuman primate models of HIV rebound. In this study, we developed an infant RM model of oral infection with simian-human immunodeficiency virus expressing clade C HIV Env and short-term ART followed by ATI, longitudinally characterizing the immune responses to viral infection during ART and after ATI. Additionally, we compared this infant RM model to an analogous adult RM rebound model and identified virologic and immunologic correlates of the time to viral rebound after ATI., To achieve long-term viral remission in human immunodeficiency virus (HIV)-infected children, novel strategies beyond early antiretroviral therapy (ART) will be necessary. Identifying clinical predictors of the time to viral rebound upon ART interruption will streamline the development of novel therapeutic strategies and accelerate their evaluation in clinical trials. However, identification of these biomarkers is logistically challenging in infants, due to sampling limitations and the potential risks of treatment interruption. To facilitate the identification of biomarkers predicting viral rebound, we have developed an infant rhesus macaque (RM) model of oral simian-human immunodeficiency virus (SHIV) SHIV.CH505.375H.dCT challenge and analytical treatment interruption (ATI) after short-term ART. We used this model to characterize SHIV replication kinetics and virus-specific immune responses during short-term ART or after ATI and demonstrated plasma viral rebound in 5 out of 6 (83%) infants. We observed a decline in humoral immune responses and partial dampening of systemic immune activation upon initiation of ART in these infants. Furthermore, we monitored SHIV replication and rebound kinetics in infant and adult RMs and found that both infants and adults demonstrated equally potent virus-specific humoral immune responses. Finally, we validated our models by confirming a well-established correlate of the time to viral rebound, namely, the pre-ART plasma viral load, as well as identified additional potential humoral immune correlates. Thus, this model of infant ART and viral rebound can be used and further optimized to define biomarkers of viral rebound following long-term ART as well as to preclinically assess novel therapies to achieve a pediatric HIV functional cure.