HIV Reservoir Ecology of Viral Remission

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ABSTRACT Among the top priorities of the HIV field is the search for therapeutic interventions that can lead to sustained antiretroviral therapy (ART)-free HIV remission. Although most HIV-infected persons will experience rapid viral rebound after ART interruption, there are rare individuals, termed post-treatment controllers (PTCs), who demonstrate sustained virologic suppression for months or years after treatment cessation. These individuals are considered an ideal example of durable HIV control, with direct implications for HIV cure research. However, our understanding of the determinants of HIV remission remains incomplete. This is in part due to the scarcity of PTCs identified through any one research center or clinical trial. To circumvent this obstacle, Dr. Jonathan Li and Colleagues have established the Control of HIV after Antiretroviral Medication Pause (CHAMP) study, the largest study of PTCs world-wide. So far, most efforts have focused on characterization of viral reservoir, latency and T-cell immune responses but numerous hurdles remain. Novel strategies to promote HIV remission are therefore warranted. It is known that HIV replication causes extensive B-cell disfunction. There is also evidence that ART improves restoration of B-cell function in PWH. The main goal of this proposal is to reveal the determinants of autologous antibody responses at play during post-treatment control of HIV replication. Antibody responses have been associated with reduced risk of HIV infection8 and spontaneous HIV control. This application builds upon Dr. Li’s recent aNAb findings and combines several unique ingredients: 1) available samples from a rare cohort of PTCs and post-treatment non- controllers (NCs), 2) HIV reservoir and sequence characterization by Dr. Li, and 3) Dr. Fofana’s demonstrated expertise in characterizing the humoral immunity and long-read sequencing. We have previously developed a phage display and long read sequencing (LRS) approach for large-scale characterization of viral-specific antibodies. More recently, the LRS protocol has been updated to characterize immunoglobulin heavy chain locus (IGH) diversity. Furthermore, using the SIV/macaque model of HIV/AIDS, we observed that non- neutralizing antibodies play a key role in slow disease progression along with viral suppression to near- undetectable levels. Here, we hypothesize that aNAb responses play a critical role in HIV suppression following ATI. Here, we propose an in-depth analysis of contemporaneous antibody responses in PTCs and NCs by way of the following specific aims: Specific Aim 1: Assess the diversity of HIV-specific antibodies in PTCs; Specific Aim 2: Capture the genetic diversity of the Immunoglobulin heavy chain in PTCs. We believe that identification of the genetic makeup of HIV-specific antibodies in PTCs and NCs will not only facilitate prediction of treatment interruption outcome but also boost the design of therapeutic antibody strategies to accompany treatment interruption and promote sustained HIV remission.