All ETDs from UAB

Advisory Committee Chair

Paul A Goepfert

Advisory Committee Members

Sonya Health

William Britt

Zdenek Hel

Louis Justement

Document Type

Dissertation

Date of Award

2020

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

In the four decades since human immunodeficiency virus (HIV) was discovered, significant progress has been made in treating HIV infection and in understanding the viral and immune dynamics underlying disease pathogenesis. However, in spite of scientific advances, HIV remains a significant global health issue, and an effective preventative vaccine has yet to be created. Many groups have demonstrated the importance of CD8 T cells in viral control during natural HIV infection and believe that CD8 T cells could contribute to vaccine efficacy by alleviating disease course in individuals who became infected despite vaccination. One major obstacle to inducing potent CD8 T-cell responses against HIV is the immense viral diversity that exists at the individual and population levels. Here we studied vaccine-induced CD8 T-cell responses in participants of two previous vaccine efficacy trials. We found that HLA-I-associated adaptation to the vaccine insert decreases both the breadth and the polyfunctionality of the vaccine-induced CD8 T-cell response. These findings are significant because breadth and polyfunctionality are two of the characteristics that have previously been linked to improved viral control and decreased infection risk, respectively. We also examined CD8 T-cell cross-reactivity, or the ability of vaccine-induced CD8 T cells to cross-recognize variant epitopes not encoded by the vaccine. These data showed that, while both vaccines induced a comparable level of CD8 T-cell cross-reactivity to what is seen in acute HIV infection, the cross-reactivity of the vaccine-induced CD8 T-cell response only influences early viral evolution in recipients who became infected and did not impact viral loads. Additionally, vaccine-induced responses were less able to recognize variants encoding HLA-I-associated adaptations. Collectively, our studies identify two significant obstacles to inducing an effective CD8 T-cell response by HIV vaccination. We hope that future vaccine studies will consider the negative effect HLA-I associated adaptation has on the overall and epitope-level CD8 T-cell responses. We also believe that our data highlight several avenues through which to boost CD8 T-cell cross-reactivity, which may be important for improving viral control in vaccine recipients who become infected.

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