Mining for humoral correlates of HIV control and latent reservoir size

Author summary Current combination antiretroviral therapy (ART) regimens have reversed the death sentence once associated with an HIV diagnosis. However, the virus is never fully eliminated. Rather, latently infected cells with integrated virus (latent reservoir) persist and the virus rebounds rapidly upon discontinuation of therapy. Further, even for those on ART, immune dysfunction, driven by persistent non-specific immune activation, ensues and progressively leads to premature immunologic aging. Current biomarkers monitoring these changes are non-specific-they focus on generic inflammatory changes that may also track with other infections or disease states. In this manuscript, we used an unbiased analytical systems approach to identify antigen-specific biomarkers of HIV disease state/treatment status, active viremia and the latent reservoir. By virtue of them being antigen-specific, these are robust context-specific biomarkers of HIV disease progression, viremia and reservoir size. Our framework highlights the strength of using systems approaches in identifying humoral biomarkers, and can be used in other contexts to identify antigen-specific correlates of infectious disease outcome. 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.