THE ROLE OF NEUTRALIZING ANTIBODIES IN PREVENTING VIRAL REBOUND FROM THE HIV-1 LATENT RESERVOIR: IMPLICATIONS FOR A CURE

Persistence of latent HIV-1 in long-lived resting memory CD4+ T cells is a major barrier to curing HIV-1 infection. Characterizing and understanding the cellular and proviral makeup of this reservoir is essential in the development of effective cure strategies. However, cell surface biomarkers that could distinguish cells comprising this latent reservoir from uninfected cells have been lacking. If identified, these biomarkers could be useful in targeting infected cells and, therefore, significantly enhance the progress towards an HIV cure. Therefore, a biomarker for latently infected cells would be of great scientific and clinical importance. Through an elegant discovery based approach, Descours et al. reported that CD32a, a Fc receptor not normally expressed on T cells, is potentially a biomarker for latently infected cells. Using the quantitative viral outgrowth assay (QVOA), we show that CD32+ CD4+ T cells do not harbor the majority of intact proviruses in the latent reservoir. We also found that the enrichment found by Descours et al. may in part reflect the use of an ultrasensitive ELISA for HIV-1 p24 antigen that does not predict exponential viral outgrowth. Our studies show that CD32 is not a biomarker for the major population of latently infected CD4+ T cells. While there are currently no known biomarkers to distinguish the latent reservoir from other resting memory CD4+ T cells, recent developments have been made in the characterization of viruses from the latent reservoir that lead to viral rebound in vivo. Moreover, recent studies by Salantes et al. and Cohen et al. have found that there is a discordance between the viruses that grow out in the QVOA and the viruses that rebound in vivo following an analytical treatment interruption (ATI). We hypothesized that immune pressure in vivo, specifically the neutralizing antibody response, could result in this discrepancy. Using the QVOA, three conditions were tested to investigate their effect on viral outgrowth: (1) standard, no IgG (2) uninfected donor IgG and (3) autologous participant IgG. Using these QVOAs, we discovered a significant reduction in viral outgrowth in the presence of participant autologous IgGs relative to outgrowth measured in uninfected donor IgG controls, suggesting rebound can be inhibited by neutralizing antibodies. Viral envelope sequences were obtained from outgrowth viruses and neutralization assays confirmed the presence of antibody resistant isolates. Using phylogenetic analysis, we also discovered primary sequence characteristics that could mediate immune escape. Elucidating the characteristics that drive immune escape among reservoir viruses will bolster our understanding of rebound dynamics during ATI. Furthermore, understanding the immune response to the expression of HIV-1 from infected cells of the latent reservoir is key to targeting these antibody resistant viruses with new HIV-1 cure strategies. Given our finding that antibodies can block outgrowth of some viruses in the reservoir, finding a way to induce antibodies or other immune responses to block outgrowth of the remaining viruses could lead to a functional cure