All ETDs from UAB

Advisory Committee Chair

Paul A Goepfert

Advisory Committee Members

Zdenek Hel

Hui Hu

Elliot Lefkowitz

Lesley Smythies

Document Type

Dissertation

Date of Award

2018

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

After nearly four decades of scientific research, a global solution in eradicating the human immunodeficiency virus - 1 (HIV-1) pandemic has still yet to be discovered. The advent of antiretroviral therapies (ART) has significantly decreased the diseases burden for those infected with the virus; however, the access to ART is often limited to those with the financial abilities to afford it. For this reason, finding a way to vaccinate against HIV-1 successfully remains a sought-after pragmatic solution to this worldwide health issue. HIV immunological studies have taught us that increasing the breadth of response to the virus holds significant potential in effectively protecting against the infection. Alternative reading frames (ARF) of HIV, in both sense and antisense directions, have been shown to produce polypeptides of unknown functions. These peptides, known as cryptic epitopes (CE), commonly induce CD8 T cell/ cytotoxic lymphocyte (CTL) responses in HIV infection and can likely increase the breadth of response to the virus. However, the role of CE in controlling HIV-1 infection remains less clear. The works in this dissertation will at-tempt to elucidate whether CD8 T cell CE responses during early HIV infection will drive the evolution of the virus, as well as present evidence which suggest CE immunity is not just limited to CTL. Under our observations, we conclude that CE play a limited role in driving adaptations associated with induced CTL responses in the setting of natural infection. We also present anecdotal evidence for novel antisense proteins by demonstrating CD4 T cell-restricted CE responses to overlapping peptides derived from anti-sense open reading frames of HIV-1. Although our data suggest that CE are not strong drivers of HIV evolution in a natural infection setting, these potential epitopes appear to be viable immunogens still as they are shown to induce responses in all arms of the adaptive immune system.

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