Abstract
While antiretroviral therapy (ART) has effectively revolutionized HIV care, the virus is never fully eliminated. Instead, immune dysfunction, driven by persistent non-specific immune activation, ensues and progressively leads to premature immunologic aging. Current biomarkers monitoring immunologic changes encompass generic inflammatory biomarkers, that may also change with other infections or disease states, precluding the antigen-specific monitoring of HIV-infection associated changes in disease. Given our growing appreciation of the significant changes in qualitative and quantitative properties of disease-specific antibodies in HIV infection, we used a systems approach to explore humoral profiles associated with HIV control. We found that HIV-specific antibody profiles diverge by spontaneous control of HIV, treatment status, viral load and reservoir size. Specifically, HIV-specific antibody profiles representative of changes in viral load were largely quantitative, reflected by differential HIV-specific antibody levels and Fc-receptor binding. Conversely, HIV-specific antibody features that tracked with reservoir size exhibited a combination of quantitative and qualitative changes marked by more distinct subclass selection profiles and unique HIV-specific Fc-glycans. Our analyses suggest that HIV-specific antibody Fc-profiles provide antigen-specific resolution on both cell free and cell-associated viral loads, pointing to potentially novel biomarkers to monitor reservoir activity.
Highlights
With rapid advances in HIV treatment over the last two decades, current combination antiretroviral therapy (ART) regimens have reversed the death sentence once associated with an HIV diagnosis [1]
We measured a total of 293 antibody features per plasma sample (S1 Table, S1 Data), including effector functions and biophysical properties, across 78 individuals (S2 Table) comprising 12 subjects who spontaneously control HIV to below detectable viremia levels (< 40 copies/ml) in the absence of ART–termed elite controllers (ECs), 23 subjects who spontaneously control HIV in the absence of ART but have detectable viremia levels (40–2000 copies/ml)–termed viremic controllers (VCs), 17 subjects on ART with undetectable viremia (CTs, < 40 copies/ ml), 12 patients not on ART with detectable viremia (CUs, >2000 copies/ml), and 14 HIV uninfected subjects
While previous data suggested that antibody features are differently correlated across different HIV clinical phenotypes [15, 20], here we used a systems approach to determine whether unique humoral profiles exist that could distinguish subjects independent of viral loads and CD4+ T cell counts
Summary
With rapid advances in HIV treatment over the last two decades, current combination antiretroviral therapy (ART) regimens have reversed the death sentence once associated with an HIV diagnosis [1]. Despite their effectiveness in reducing viral replication, and associated loss of CD4+ T cells, the virus is never completely eradicated. The virus rebounds rapidly upon discontinuation of therapy Along these lines, even on suppressive ART, infection-associated transcription, in the absence of replication, may persist. While several inflammatory markers have been identified that track with persisting viral activity or the latent reservoir size itself, a quantifiable antigen-specific biomarker that provides insight on viral activity, deep within tissues, could provide critical insights to prevent the continued morbidity observed with HIV treatment [3]
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