Date of Award

2018

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

Katharine J. Bar

Abstract

In HIV-infected patients, combination antiretroviral therapy (cART) during HIV-1 infection potently suppresses viral replication and slows progression to AIDS. Upon cessation of cART, however, systemic infection is rapidly re-established due to the long-lived pool of latently infected cells, or HIV reservoir, that is seeded early in infection and persists despite years of cART in patients. This long-lived reservoir is the target of novel curative strategies. In order to determine in vivo efficacy of these interventions, closely monitored analytical treatment interruption (ATI) is required. Previously conducted ATI trials have provided important baseline information regarding the kinetics and diversity of viruses emerging from latency. As future HIV curative clinical trials move towards prolonged periods of ATI, studies assessing the effect of ATI on host virus-immune dynamics will provide an important baseline that will further our understanding of trial outcomes. In this thesis, I conducted single genome sequencing (SGS) of HIV-1 env and neutralization assays using autologous antibodies to characterize the viral and immune dynamics of rebound in two clinical trials: a longitudinal ATI study in the absence of any intervention, and a brief ATI study involving administration of the broadly neutralizing antibody VRC01. Our data, consistent with previous studies, demonstrated that viral rebound occurs within four weeks of ATI and is established by multiple latently infected cells in the majority of HIV-infected participants. Analyses of plasma containing VRC01 and/or autologous antibodies show that latent reservoir viruses can experience an antibody-mediated neutralization sieve effect, thus preventing the persistence of antibody-sensitive viruses. Additionally, SGS of latent viruses before and after brief ATI show that the size and composition of the peripheral latent viral reservoir is not significantly altered during ATI, demonstrating that short-term ATI is safe. Taken together, these data highlight the complex virus-host dynamics during ATI, and further suggest that passively infused or host-derived neutralizing antibodies can exert selective pressure, altering the evolution of HIV in its host.

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