Project 3 - Dynamics of latent HIV-1 reservoirs: High resolution antigenic mapping and strategies to block rebound

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Abstract – Project 3 Approximately 40 million people worldwide are living with HIV/AIDS; however, a protective vaccine or functional cure remain elusive despite four decades of intense research. HIV-1 evades the immune system through its rapid structural evolution during infection and replication. The latent reservoir in resting memory (RM) CD4+ T cells is the major barrier to curing HIV-1 infection. Established early during infection, the latent reservoir is extremely stable, and persists despite long-term antiretroviral therapy (ART). When latently infected RM CD4+ T cells are activated in vivo, they can begin to produce HIV virions again, resulting in exponential viral growth and rebound viremia if ART has been interrupted. Eradicating this latent viral reservoir to achieve cure from HIV- 1 has been a long-sought goal that has been difficult to achieve. An alternate approach is to delay or reduce rebound from latent reservoirs allowing sustained ART-free remission. A recent study from the Siliciano lab has shown that autologous neutralizing antibodies (anAbs) directed at the HIV-1 Envelope (Env) protein suppress outgrowth of a substantial but variable fraction of reservoir viruses in vitro. This effect was attributed to neutralizing activity of anAbs, and provides proof-of-principle for the feasibility of Ab-mediated prevention of viral rebound from latent reservoirs. Moreover, by demonstrating that anAbs block the outgrowth of a substantial population of the replication-competent viruses in the latent reservoir, these results effectively reduce the magnitude of the problem of controlling rebound to the subset of reservoir viruses that are resistant to anAbs. In this project, we will visualize the binding of anAbs to the Envs of sensitive viruses. Further, we will determine atomic level structures of Envs from the viruses resistant to anAbs to understand the molecular basis for their resistance, and to define their vulnerabilities. Thus, the overall goal of this study is an atomic level understanding of antibody-mediated control of rebound from latent HIV-1 reservoirs. To achieve this goal, we will aim to 1) define the epitope specificities of anAbs that suppress outgrowth of a substantial population of the replication- competent proviruses in the latent HIV-1 reservoir; 2) define mechanisms of resistance of rebound viruses to neutralization by anAbs; and 3) define the evolution of the anAb response in HIV-1 infected individuals to understand its effect on the seeding of the latent reservoir and its impact on rebound viremia. At the culmination of this study, we expect to have defined, structurally and antigenically, the common features of the anAb resistant Envs that the can be targeted to prevent rebound.