HIV escape mutations occur preferentially at HLA-binding sites of CD8 T-cell epitopes.

TitleHIV escape mutations occur preferentially at HLA-binding sites of CD8 T-cell epitopes.
Publication TypeJournal Article
Year of Publication2013
AuthorsBronke C, Almeida C-AM, McKinnon E, Roberts SG, Keane NM, Chopra A, Carlson JM, Heckerman D, Mallal S, John M
JournalAIDS
Volume27
Issue6
Pagination899-905
Date Published2013 Mar 27
ISSN1473-5571
KeywordsBinding Sites, Epitopes, T-Lymphocyte, HIV-1, Humans, Immune Evasion, Mutation, Missense, Phosphoproteins, Polymorphism, Genetic, Protein Binding
Abstract

OBJECTIVE: To define the relative frequencies of different mechanisms of viral escape.

DESIGN: A population-based approach to examine the distribution of HIV polymorphism associated with diverse population human leucocyte antigens (HLAs) at sites within and flanking CD8 T-cell epitopes as a correlate of likely mechanisms of viral escape.

METHODS: Sequence windows surrounding 874 HLA allele-specific polymorphisms across the full HIV-1 proteomic consensus sequence were scanned by an epitope-prediction programme. Either already known or probable CD8 T-cell epitopes with HLA restriction matching that of the proximal HLA association were identified and synthesized. These peptides were used as stimulating antigens in automated enzyme-linked immunospot (ELISpot) assays. Peptide arrays were customized to each individual based on their HLA genotype.

RESULTS: Among HLA-associated HIV polymorphisms detected in the viral sequences of a cohort of 800 individuals with chronic subtype B HIV infection, those which were likely to affect HLA peptide binding were significantly more common than polymorphisms at nonanchor HLA binding sites. HIV epitopes with such polymorphisms were associated with reduced IFNγ responses in ELISpot assays. HIV escape at sites affecting T-cell receptor (TCR) engagement and epitope processing were also evident.

CONCLUSION: HIV escape from HLA-peptide binding predominates as an effective viral evasion strategy and therefore has implications for inclusion of HLA-adapted epitopes in vaccine immunogens.

DOI10.1097/QAD.0b013e32835e1616
Alternate JournalAIDS
PubMed ID23276808
PubMed Central IDPMC3818524
Grant ListAI-68636 / AI / NIAID NIH HHS / United States
AI046376 / AI / NIAID NIH HHS / United States
AI069419 / AI / NIAID NIH HHS / United States
AI069424 / AI / NIAID NIH HHS / United States
AI069432 / AI / NIAID NIH HHS / United States
AI069434 / AI / NIAID NIH HHS / United States
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AI069471 / AI / NIAID NIH HHS / United States
AI069472 / AI / NIAID NIH HHS / United States
AI069474 / AI / NIAID NIH HHS / United States
AI069477 / AI / NIAID NIH HHS / United States
AI069484 / AI / NIAID NIH HHS / United States
AI069495 / AI / NIAID NIH HHS / United States
AI069501 / AI / NIAID NIH HHS / United States
AI069502 / AI / NIAID NIH HHS / United States
AI069513 / AI / NIAID NIH HHS / United States
AI069532 / AI / NIAID NIH HHS / United States
AI069556 / AI / NIAID NIH HHS / United States
AI25859 / AI / NIAID NIH HHS / United States
AI27661 / AI / NIAID NIH HHS / United States
AI27673 / AI / NIAID NIH HHS / United States
AI32782 / AI / NIAID NIH HHS / United States
AI34853 / AI / NIAID NIH HHS / United States
AI38858 / AI / NIAID NIH HHS / United States
AI46370 / AI / NIAID NIH HHS / United States
AI64086 / AI / NIAID NIH HHS / United States
AI68634 / AI / NIAID NIH HHS / United States
AI68636 / AI / NIAID NIH HHS / United States
AI69411 / AI / NIAID NIH HHS / United States
AI69423 / AI / NIAID NIH HHS / United States
AI69465 / AI / NIAID NIH HHS / United States
AI69467 / AI / NIAID NIH HHS / United States
AI69494 / AI / NIAID NIH HHS / United States
R01 AI060460 / AI / NIAID NIH HHS / United States
R01 AI060460 / AI / NIAID NIH HHS / United States
RR024975 / RR / NCRR NIH HHS / United States
UM1 AI069423 / AI / NIAID NIH HHS / United States