Publication Date:
2010-05-07
Description:
Without therapy, most people infected with human immunodeficiency virus (HIV) ultimately progress to AIDS. Rare individuals ('elite controllers') maintain very low levels of HIV RNA without therapy, thereby making disease progression and transmission unlikely. Certain HLA class I alleles are markedly enriched in elite controllers, with the highest association observed for HLA-B57 (ref. 1). Because HLA molecules present viral peptides that activate CD8(+) T cells, an immune-mediated mechanism is probably responsible for superior control of HIV. Here we describe how the peptide-binding characteristics of HLA-B57 molecules affect thymic development such that, compared to other HLA-restricted T cells, a larger fraction of the naive repertoire of B57-restricted clones recognizes a viral epitope, and these T cells are more cross-reactive to mutants of targeted epitopes. Our calculations predict that such a T-cell repertoire imposes strong immune pressure on immunodominant HIV epitopes and emergent mutants, thereby promoting efficient control of the virus. Supporting these predictions, in a large cohort of HLA-typed individuals, our experiments show that the relative ability of HLA-B alleles to control HIV correlates with their peptide-binding characteristics that affect thymic development. Our results provide a conceptual framework that unifies diverse empirical observations, and have implications for vaccination strategies.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3098720/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3098720/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kosmrlj, Andrej -- Read, Elizabeth L -- Qi, Ying -- Allen, Todd M -- Altfeld, Marcus -- Deeks, Steven G -- Pereyra, Florencia -- Carrington, Mary -- Walker, Bruce D -- Chakraborty, Arup K -- DP1 OD001022/OD/NIH HHS/ -- DP1 OD001022-04/OD/NIH HHS/ -- HHSN261200800001E/CA/NCI NIH HHS/ -- HHSN261200800001E/PHS HHS/ -- P30 AI060354/AI/NIAID NIH HHS/ -- R01 AI030914/AI/NIAID NIH HHS/ -- R01 AI030914-07/AI/NIAID NIH HHS/ -- R01 AI030914-09/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- Intramural NIH HHS/ -- England -- Nature. 2010 May 20;465(7296):350-4. doi: 10.1038/nature08997. Epub 2010 May 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts 02114, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20445539" target="_blank"〉PubMed〈/a〉
Keywords:
Algorithms
;
Alleles
;
Autoantigens/immunology
;
CD8-Positive T-Lymphocytes/*cytology/*immunology
;
Cohort Studies
;
Cross Reactions/immunology
;
Disease Progression
;
Genes, MHC Class I/genetics/immunology
;
HIV Infections/*immunology
;
HIV-1/chemistry/genetics/growth & development/immunology
;
HLA-B Antigens/genetics/*immunology
;
Host-Pathogen Interactions/immunology
;
Humans
;
Immunodominant Epitopes
;
Models, Immunological
;
Protein Binding
;
Thymus Gland/cytology/*immunology
;
Viral Load/immunology
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
