All ETDs from UAB

Advisory Committee Chair

Paul A Goepfert

Advisory Committee Members

Randy Q Cron

Sonya L Heath

Zdenek Hel

Randall Davis

Document Type

Dissertation

Date of Award

2016

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

It is well known that CD8 T cells play an important role in viral control. Many viruses, including human immunodeficiency virus-1 (HIV-1), escape from CD8 T-cell mediated immune pressure. Increasing number of studies have suggested that CD4 T cells, usually considered as primary targets of HIV-1 infection, can also play an active antiviral role and hence can drive viral escape like their CD8 counterparts. The works presented in this dissertation examined the impact of transmitted HIV-1 escapes on CD8 T-cell responses and clinical outcomes following infection, the ability of CD8 T cells to cross-recognize viral variants during acute infection, and HIV-1 escapes associated with CD4 T cells. Our results indicate that transmission of viruses with many escape mutations reduces recognition by the initial antiviral CD8 T cells during acute infection and predicts subsequent loss of viral control, as evidenced by elevated set-point viral load and precipitated CD4 decline. Furthermore, we find that CD8 T cells are poorly crossreactive during acute HIV-1 infection, as demonstrated by reduced immunogenicity of epitope variants and poor cytotoxicity of T cells targeting these variants. Mechanistically, the impaired cross-reactive response is explained by compromised Tcell receptor (TCR) recognition of antigenic variants. In addition, by utilizing methods to predict mutations associated with human leukocyte antigen (HLA) class II (HLA-II) restricted CD4 T cells, similar to what were done for HLA class I (HLA-I) mutations for the CD8, we demonstrate evidence that CD4 T cells can mediate viral escape as well. In sum, our work shows that HIV-1 adapts to exploit deficiencies in the immune system involving two main types of T cells, compromising CD8 and CD4 T-cell recognition for its survival advantage. The study thus presents important implications for future T-cell based vaccine development that seeks to optimize vaccine-induced responses.

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