All ETDs from UAB

Advisory Committee Chair

Paul A Goepfert

Advisory Committee Members

William J Britt

David D Chaplin

Robin G Lorenz

Peter E Prevelige

Document Type

Dissertation

Date of Award

2011

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

In the absence of antiretroviral therapy (ART), the majority of individuals infected with human immunodeficiency virus-1 (HIV-1) will develop AIDS. HIV-1-infected controllers are exceptions to the rule; without the use of ART, these individuals spontaneously control virus replication. A better understanding of the immune mechanisms that mediate delayed disease progression, as seen in controllers, will provide valuable insight to the design and development of an effective HIV-1 vaccine. CD8 T cells are important mediators of the antiviral immune response. However, it is unclear which components of the response are critical for long-lasting protection during HIV-1 infection. We first review methods currently used in the analysis of HIV-1-specific CD8 T cell function. We then discuss our analysis of HIV-1-specific CD8 T cell clonal populations that did or did not produce interleukin-2 (IL-2), an effector function associated with delayed disease progression. Having observed a unique clonotypic profile of IL-2 producing CD8 T cells, we predicted that maintenance of IL-2 production identifies a population of CD8 T cells with enhanced ability to (1) produce antiviral soluble factors as observed using multicolor flow cytometry and (2) restrict HIV-1 replication as detected using an in vitro suppression assay (iVSA). To test this hypothesis, we analyzed epitope-specific CD8 T cell function first during chronic HIV-1 infection and subsequently during primary infection. Using the iVSA, we observed significantly enhanced suppression of HIV-1 replication by CD8 T cells derived from controllers when compared to progressors. Interestingly, the level of suppression correlated with a polyfunctional, IL-2+ CD8 T cell response. Preliminary results of CD8 T cell effector function during primary HIV-1 disease show that functional, epitope-specific CD8 T cell lines can be expanded and these cells are able to suppress HIV-1 replication in vitro, albeit to moderate levels. Both the proliferative and suppressive capacity of CD8 T cells derived from the early stage of disease appeared to increase over time. These studies suggest that suppression of HIV-1 replication and polyfunctional IL-2 production would be promising markers of an effective CD8 T cell response and have important implications for the evaluation of HIV-1 vaccine strategies.

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