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


Date of Award


Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine


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.