Journal article
Evolution of HLA-B5703 HIV-1 escape mutations in HLA-B5703-positive individuals and their transmission recipients
The Journal of experimental medicine, Vol.206(4), pp.909-921
04/13/2009
DOI: 10.1084/jem.20081984
PMCID: PMC2715113
PMID: 19307327
Abstract
HLA-B*57 is the class I allele most consistently associated with control of human immunodeficiency virus (HIV) replication, which may be linked to the specific HIV peptides that this allele presents to cytotoxic T lymphocytes (CTLs), and the resulting efficacy of these cellular immune responses. In two HIV C clade-infected populations in South Africa and Zambia, we sought to elucidate the role of HLA-B*5703 in HIV disease outcome. HLA-B*5703 restricted CTL responses select for escape mutations in three Gag p24 epitopes, in a predictable order. We show that the accumulation of these mutations sequentially reduces viral replicative capacity in vitro. Despite this, in vivo data demonstrate that there is ultimately an increase in viral load concomitant with evasion of all three HLA-B*5703-restricted CTL responses. In HLA-B*5703-mismatched recipients, the previously described early benefit of transmitted HLA-B*5703-associated escape mutations is abrogated by the increase in viral load coincident with reversion. Rapid disease progression is observed in HLA-matched recipients to whom mutated virus is transmitted. These data demonstrate that, although costly escape from CTL responses can progressively attenuate the virus, high viral loads develop in the absence of adequate, continued CTL responses. These data underline the need for a CTL vaccine against multiple conserved epitopes.
Details
- Title: Subtitle
- Evolution of HLA-B5703 HIV-1 escape mutations in HLA-B5703-positive individuals and their transmission recipients
- Creators
- Hayley Crawford - University of OxfordWendy Lumm - Emory UniversityAlasdair Leslie - University of OxfordMalinda Schaefer - Emory UniversityDebrah Boeras - Emory UniversityJulia G. Prado - University of OxfordJianming Tang - University of Alabama at BirminghamPaul Farmer - Emory and Henry CollegeThumbi Ndung'u - University of KwaZulu-NatalShabir Lakhi - Emory and Henry CollegeJill Gilmour - Chelsea and Westminster HospitalPaul Goepfert - University of Alabama at BirminghamBruce D. Walker - Massachusetts General HospitalRichard Kaslow - University of Alabama at BirminghamJoseph Mulenga - Emory and Henry CollegeSusan Allen - Emory UniversityPhilip J. R. Goulder - University of OxfordEric Hunter - Emory University
- Resource Type
- Journal article
- Publication Details
- The Journal of experimental medicine, Vol.206(4), pp.909-921
- Publisher
- Rockefeller Univ Press
- DOI
- 10.1084/jem.20081984
- PMID
- 19307327
- PMCID
- PMC2715113
- ISSN
- 0022-1007
- eISSN
- 1540-9538
- Number of pages
- 13
- Grant note
- AI-64060; AI-46995; AI-067073 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA Wellcome Trust International AIDS Vaccine Initiative 37874 / Bill & Melinda Gates Foundation; Bill & Melinda Gates Foundation Grand Challenges Explorations Initiative; CGIAR Department for International Development and the Commonwealth Scholarship Commission Elizabeth Glaser Pediatric AIDS Foundation
- Language
- English
- Date published
- 04/13/2009
- Academic Unit
- Obstetrics and Gynecology
- Record Identifier
- 9984697044102771
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