Viral Rebound Kinetics Correlate with Distinct HIV Antibody Features.

Yannic C Bartsch,Jintanat Ananworanich,Galit Alter,Sasiwimol Ubolyam,Bernard Hirschel,Carolin Loos,Dansu Yuan,Boris Julg,Thidarat Jupimai,Douglas A Lauffenburger,Jonathan Z Li,Anchalee Avihingsanon,Evan Rossignol,Jesse M Fajnzylber,Salim Abdool Karim

doi:10.1128/mbio.00170-21

Abstract

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.

Highlights

Plasma viremia reoccurs in most Human immunodeficiency virus (HIV)-infected individuals once antiretroviral therapy (ART) is interrupted
We investigated HIV-specific antibody profiles in plasma from 23 ART-suppressed HIV-infected individuals, who had been enrolled in Thailand as part of the STACCATO trial, a CD4 T-cell count-guided analytical antiretroviral treatment interruption study [17]
The groups did not differ in age or baseline CD4 counts, the time it took during ART interruption (ATI) for detectable plasma HIV RNA to occur (#4 weeks versus .4 weeks to rebound), separated them in a principal-component analysis

Summary

Introduction

Plasma viremia reoccurs in most HIV-infected individuals once antiretroviral therapy (ART) is interrupted. 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. Immune activation by itself can promote HIV transcription and virus production [5] and supports HIV persistence by inducing continuous proliferation of latently infected cells [6] The complexity of these relationships has made it difficult to measure/quantify the overall inflammatory state and the level of activation of the viral reservoir in individuals on ART, both of which are likely to be insufficiently captured in the usual clinical measurements of CD4 T-cell counts and plasma HIV RNA levels.

Methods

Results

Conclusion