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Neutralizing antibody VRC01 failed to select for HIV-1 mutations upon viral rebound.

ABSTRACT: Infusion of the broadly neutralizing antibody VRC01 has been evaluated in individuals chronically infected with HIV-1. Here, we studied how VRC01 infusions affected viral rebound after cessation of antiretroviral therapy (ART) in 18 acutely treated and durably suppressed individuals. Viral rebound occurred in all individuals, yet VRC01 infusions modestly delayed rebound and participants who showed a faster decay of VRC01 in serum rebounded more rapidly. Participants with strains most sensitive to VRC01 or with VRC01 epitope motifs similar to known VRC01-susceptible strains rebounded later. Upon rebound, HIV-1 sequences were indistinguishable from those sampled at diagnosis. Across the cohort, participant-derived Env showed different sensitivity to VRC01 neutralization (including 2 resistant viruses), yet neutralization sensitivity was similar at diagnosis and after rebound, indicating the lack of selection for VRC01 resistance during treatment interruption. Our results showed that viremia rebounded despite the absence of HIV-1 adaptation to VRC01 and an average VRC01 trough of 221 ?g/mL. Although VRC01 levels were insufficient to prevent a resurgent infection, knowledge that they did not mediate Env mutations in acute-like viruses is relevant for antibody-based strategies in acute infection.

SUBMITTER: Cale EM

PROVIDER: S-EPMC7259993 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Neutralizing antibody VRC01 failed to select for HIV-1 mutations upon viral rebound.

Cale Evan M EM Bai Hongjun H Bose Meera M Messina Michael A MA Colby Donn J DJ Sanders-Buell Eric E Dearlove Bethany B Li Yifan Y Engeman Emily E Silas Daniel D O'Sullivan Anne Marie AM Mann Brendan B Pinyakorn Suteeraporn S Intasan Jintana J Benjapornpong Khunthalee K Sacdalan Carlo C Kroon Eugène E Phanuphak Nittaya N Gramzinski Robert R Vasan Sandhya S Robb Merlin L ML Michael Nelson L NL Lynch Rebecca M RM Bailer Robert T RT Pagliuzza Amélie A Chomont Nicolas N Pegu Amarendra A Doria-Rose Nicole A NA Trautmann Lydie L Crowell Trevor A TA Mascola John R JR Ananworanich Jintanat J Tovanabutra Sodsai S Rolland Morgane M

The Journal of clinical investigation 20200601 6

Infusion of the broadly neutralizing antibody VRC01 has been evaluated in individuals chronically infected with HIV-1. Here, we studied how VRC01 infusions affected viral rebound after cessation of antiretroviral therapy (ART) in 18 acutely treated and durably suppressed individuals. Viral rebound occurred in all individuals, yet VRC01 infusions modestly delayed rebound and participants who showed a faster decay of VRC01 in serum rebounded more rapidly. Participants with strains most sensitive t ...[more]

PMID: 32182219

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Project description:BACKGROUND:The discovery of potent and broadly neutralizing antibodies (bNAbs) against human immunodeficiency virus (HIV) has made passive immunization a potential strategy for the prevention and treatment of HIV infection. We sought to determine whether passive administration of VRC01, a bNAb targeting the HIV CD4-binding site, can safely prevent or delay plasma viral rebound after the discontinuation of antiretroviral therapy (ART). METHODS:We conducted two open-label trials (AIDS Clinical Trials Group [ACTG] A5340 and National Institutes of Health [NIH] 15-I-0140) of the safety, side-effect profile, pharmacokinetic properties, and antiviral activity of VRC01 in persons with HIV infection who were undergoing interruption of ART. RESULTS:A total of 24 participants were enrolled, and one serious alcohol-related adverse event occurred. Viral rebound occurred despite plasma VRC01 concentrations greater than 50 ?g per milliliter. The median time to rebound was 4 weeks in the A5340 trial and 5.6 weeks in the NIH trial. Study participants were more likely than historical controls to have viral suppression at week 4 (38% vs. 13%, P=0.04 by a two-sided Fisher's exact test in the A5340 trial; and 80% vs. 13%, P<0.001 by a two-sided Fisher's exact test in the NIH trial) but the difference was not significant at week 8. Analyses of virus populations before ART as well as before and after ART interruption showed that VRC01 exerted pressure on rebounding virus, resulting in restriction of recrudescent viruses and selection for preexisting and emerging antibody neutralization-resistant virus. CONCLUSIONS:VRC01 slightly delayed plasma viral rebound in the trial participants, as compared with historical controls, but it did not maintain viral suppression by week 8. In the small number of participants enrolled in these trials, no safety concerns were identified with passive immunization with a single bNAb (VRC01). (Funded by the National Institute of Allergy and Infectious Diseases and others; ACTG A5340 and NIH 15-I-0140 ClinicalTrials.gov numbers, NCT02463227 and NCT02471326 .).

Project description:Plasma viremia reoccurs in most HIV-infected individuals once antiretroviral therapy (ART) is interrupted. The kinetics of viral rebound, specifically the time until plasma virus becomes detectable, differ quite substantially between individuals, and associations with virological and immunological factors have been suggested. Standard clinical measures, like CD4 T-cell counts and plasma HIV RNA levels, however, are poor predictive markers. Antibody features, including Fc functionality and Fc glycosylation have been identified as sensitive surrogates for disease activity in multiple diseases. Here, we analyzed HIV-specific antibody quantities and qualitative differences like antibody-mediated functions, Fc gamma receptor (FcγR) binding, and IgG Fc glycosylation as well as cytokine profiles and cellular HIV DNA and RNA levels in 23 ART-suppressed individuals prior to undergoing an analytical ART interruption (ATI). We found that antibodies with distinct functional properties and Fc glycan signatures separated individuals into early and delayed viral rebounders (≤4 weeks versus >4 weeks) and tracked with levels of inflammatory cytokines and transcriptional activity of the viral reservoir. Specifically, individuals with early viral rebound exhibited higher levels of total HIV-specific IgGs carrying inflammatory Fc glycans, while delayed rebounders showed an enrichment of highly functional antibodies. Overall, only four features, including enhanced antibody-mediated NK cell activation in delayed rebounders, were necessary to discriminate the groups. These data suggest that antibody features can be used as sensitive indicators of HIV disease activity and could be included in future ATI studies.IMPORTANCE Plasma viremia reoccurs in most HIV-infected individuals once antiretroviral therapy is interrupted, and interindividual differences in the kinetics of viral rebound have been associated with virological and immunological factors. Antibody features, including Fc functionality and Fc glycosylation, have been identified as sensitive surrogates for disease activity in multiple diseases. Here, we systematically analyzed HIV-specific antibody quantities and qualitative differences in 23 ART-suppressed individuals prior to undergoing an analytical ART interruption (ATI). We found that antibodies with distinct functional properties and Fc glycan signatures separated individuals into early and delayed viral rebounders and tracked with levels of inflammatory cytokines and transcriptional activity of the viral reservoir. These data suggest that antibody features can be used as sensitive indicators of HIV disease activity and could be included in future HIV eradication studies.

Project description:ObjectiveHIV cure research urgently needs to identify pre-analytic treatment interruption (ATI) biomarkers of time-to-viral-rebound and viral setpoint to mitigate the risk of ATI and accelerate development of a cure. We previously reported that galactosylated IgG glycans, G2, negatively correlate with cell-associated HIV DNA and RNA during antiretroviral therapy (ART). We hypothesized that this and other plasma glycomic traits can predict time-to-viral-rebound and viral setpoint upon ART cessation.DesignWe profiled the circulating glycomes (plasma and bulk IgG) of two geographically distinct cohorts: Philadelphia Cohort - 24 HIV-infected, ART-suppressed individuals who had participated in an open-ended ATI study without concurrent immunomodulatory agents. Johannesburg Cohort - 23 HIV-infected, ART-suppressed individuals who had participated in a 2-week ATI.MethodsCapillary electrophoresis and lectin microarray were used for glycomic analyses. Cox proportional-hazards model and log-rank test were used for statistical analyses.ResultsHigher pre-ATI levels of the IgG glycan, G2, were significantly associated with a longer time-to-viral-rebound (hazard ratio = 0.12, P = 0.05). In addition to G2, we identified several predictive glycomic traits in plasma, for example, levels of FA2BG1, a non-sialylated, core-fucosylated glycan, associated with a longer time-to-viral-rebound (hazard ratio = 0.023, P = 0.05), whereas FA2G2S1, a sialylated glycan, associated with a shorter time-to-viral-rebound (hazard ratio = 24.1, P = 0.028). Additionally, pre-ATI plasma glycomic signatures associated with a lower viral setpoint, for example, T-antigen (Galβ1-3GalNAc) (r = 0.75, P = 0.0007), or a higher viral setpoint, for example, polylactosamine (r = -0.58, P = 0.01). These results were initially validated in the Johannesburg Cohort.ConclusionWe describe first-in-class, non-invasive, plasma and IgG glycomic biomarkers that inform time-to-viral-rebound and viral setpoint in two geographically distinct cohorts.

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Neutralizing antibody VRC01 failed to select for HIV-1 mutations upon viral rebound.

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Neutralizing antibody VRC01 failed to select for HIV-1 mutations upon viral rebound.

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