Assessing the longitudinal impact of VRC01 prophylaxis on viral populations and autologous antibody responses in breakthrough infections

About This Grant

Summary Despite significant progress in combating HIV, an effective vaccine is still elusive. On the other hand, passive immunization with broadly neutralizing antibodies (bnAbs) used in therapy or prophylaxis show promise in reducing in complementing current antiretroviral therapies (ART) and reducing the rate of new infections. However, more work is needed in understanding viral resistance to bnAbs and bnAb escape, as well as the effect of bnAbs on immune responses. Our overarching goal is to investigate the impact of the presence of the monoclonal bnAb VRC01 at HIV acquisition on viral diversity and host antibody responses. We hypothesize that if VRC01 prophylaxis has immunomodulatory effects on breakthrough infections, we would observe lower viral diversity at rebound after treatment interruption and/or earlier emergence of neutralizing autologous antibody responses in VRC01 recipients compared to placebo. We will address these questions by leveraging longitudinal data (anticipated and already acquired) from the Antibody Mediated Protection (AMP) trial HVTN 704 and the follow-up Analytic Treatment Interruption (ATI) trial HVTN 804, which enrolled study participants from Lima, Peru. These trials were designed to assess immunologic and virologic responses during ART interruption in AMP study participants who acquired HIV while receiving either placebo or VRC01 prophylaxis and started ART shortly after infection. This proposal addresses analyses not currently funded by the HIV Vaccine Trial Network (HVTN) that are nonetheless critical to understand the immunomodulatory function of passively administered bnAbs in both therapy and prophylaxis. Understanding the impact of VRC01 on autologous immune responses and intra-host viral evolution will inform ongoing and upcoming clinical trials testing bnAb therapy and prevention and help devise strategies to minimize bnAb escape while harnessing the potential benefit of immune enhancement. Analysis of high-throughput deep sequencing data will allow detection of rebound lineages at higher resolution compared to previous studies, especially transitory low-frequency lineages that may have otherwise gone undetected and could offer important clues on the selective pressures acting on the virus.