All ETDs from UAB

Advisory Committee Chair

Paul A Goepfert

Advisory Committee Members

Casey D Morrow

Allan J Zajac

Elliot J Lefkowitz

Zdenek Hel

Document Type

Dissertation

Date of Award

2014

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Cryptic epitopes (CE) are a unique set of human leukocyte antigen class I (HLA-I)-restricted peptides that are encoded by alternative reading frames (ARFs) of genes. During human immunodeficiency virus-1 (HIV-1) infection, CE translated from either sense or antisense transcripts elicit epitope-specific CD8 T cell responses. Previous studies using simian immunodeficiency virus (SIV)-vaccinated animals have shown that an increased breadth of CD8 T cell responses is correlated with controlling viral replication, therefore stressing the potential clinical benefit of vaccine-induced T cell responses to a diverse set of viral epitopes. Yet, the genetic profiles and immunological significance of CE remain poorly understood. The work presented herein describes the recognition of HIV-1 CE during infection and following vaccination. Using bioinformatic tools, a preliminary analysis of coding strategies for vaccine vectors revealed a striking reduction in the amino acid identity of ARF sequences following codon optimization. I therefore evaluated the induction of T cell responses to CE in recipients of a noncodon-optimized HIV-1 vaccine (MVA/HIV62). My ex vivo analysis showed near-threshold positive responses to CE in both the vaccine and placebo groups. However, in vitro expansion of virus-specific T cells allowed for detection of high-magnitude responses to CE in vaccine but not placebo recipients. These findings represent the first demonstration of vaccine-induced T cell responses to CE in a human clinical trial. As a continuation of my research on novel HIV-1 ARF immunogens, I evaluated the immunogenicity of antigens expressed from a conserved, open reading frame found in an antisense ARF of HIV-1 env, or so called Antisense Protein (ASP). T cell responses to HLA-I-restricted ASP antigens were studied in chronically-infected HIV-1-positive patients. My results showed that ASP-derived epitopes were specifically recognized by CD8 T cells from patients who expressed the appropriate HLA-I molecules. This work provides further evidence for the existence of ASP and indicates that some CE are biomarkers of transcriptionally active viral ARFs. In sum, my dissertation research highlighted the immunological relevance of CE and suggests that future HIV-1 vaccines may be enhanced by prioritizing expression of ARF immunogens to increase to total number of potential T cell targets.

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