Date of Award

2016

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

Michael R. Betts

Abstract

A detailed understanding of the immune response to human immunodeficiency virus (HIV) infection is needed to inform prevention and therapeutic strategies that aim to contain the AIDS pandemic. The CD8+ T cell response plays a critical role in controlling viral replication during HIV infection and will likely need to be a part of any vaccine approach. The qualitative feature of the CD8+ T cell response most closely associated with immunologic control of HIV infection is its cytotoxic capacity. The pore-forming protein, perforin, is a major determinant of the cytotoxic capacity of CD8+ T cells. In the context of chronic HIV infection, enhanced perforin expression by HIV-specific CD8+ T cells is associated with greater control over HIV replication. However, individuals experiencing chronic progressive infection (CP) often demonstrate a diminished ability to express this important cytolytic molecule. HIV-specific CD8+ T cells from CP also express lower levels of the T-box transcription factor T-bet, an upstream regulator of CD8+ T cell effector differentiation and function. Whether HIV-specific CD8+ T cells from progressors possess effector capacity during the earliest stages of infection and subsequently lose it remains unclear. The relationship between perforin, T-bet, and the closely related transcription factor eomesodermin (Eomes) also remains largely undefined in the context of acute, chronic, or controlled HIV infection. In this work, we report that CD8+ T cell responses had high cytotoxic potential during acute HIV infection but perforin expression quickly waned with the resolution of peak viremia. Importantly, perforin was maintained in HIV-specific CD8+ T cells with high levels of T-bet, but not necessarily in a population of T-betLo HIV-specific CD8+ T cells that expanded as infection progressed. During chronic infection there was a generalized increase in perforin expression for both total memory and HIV-specific CD8+ T cells that was dissociated from both T-bet and Eomes. Of note, however, individuals in which perforin remained closely associated with T-bet demonstrated greater in vivo control of HIV replication. Collectively, our data imply that loss of transcriptional regulators responsible for driving strong cytotoxic responses, such as T-bet, contributes to CD8+ T cell dysfunction during chronic progressive HIV infection.

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