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High frequency of HIV mutations associated with HLA-C suggests enhanced HLA-C-restricted CTL selective pressure associated with an AIDS-protective polymorphism.

Abstract
Delayed HIV-1 disease progression is associated with a single nucleotide polymorphism upstream of the HLA-C gene that correlates with differential expression of the HLA-C Ag. This polymorphism was recently shown to be a marker for a protective variant in the 3'UTR of HLA-C that disrupts a microRNA binding site, resulting in enhanced HLA-C expression at the cell surface. Whether individuals with "high" HLA-C expression show a stronger HLA-C-restricted immune response exerting better viral control than that of their counterparts has not been established. We hypothesized that the magnitude of the HLA-C-restricted immune pressure on HIV would be greater in subjects with highly expressed HLA-C alleles. Using a cohort derived from a unique narrow source epidemic in China, we identified mutations in HIV proviral DNA exclusively associated with HLA-C, which were used as markers for the intensity of the immune pressure exerted on the virus. We found an increased frequency of mutations in individuals with highly expressed HLA-C alleles, which also correlated with IFN-γ production by HLA-C-restricted CD8(+) T cells. These findings show that immune pressure on HIV is stronger in subjects with the protective genotype and highlight the potential role of HLA-C-restricted responses in HIV control. This is, to our knowledge, the first in vivo evidence supporting the protective role of HLA-C-restricted responses in nonwhites during HIV infection.
AuthorsMarie-Eve Blais, Yonghong Zhang, Tim Rostron, Harry Griffin, Stephen Taylor, Keyi Xu, Huiping Yan, Hao Wu, Ian James, Mina John, Tao Dong, Sarah L Rowland-Jones
JournalJournal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 188 Issue 9 Pg. 4663-70 (May 01 2012) ISSN: 1550-6606 [Electronic] United States
PMID22474021 (Publication Type: Clinical Trial, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
Chemical References
  • 3' Untranslated Regions
  • DNA, Viral
  • HLA-C Antigens
  • Interferon-gamma
Topics
  • 3' Untranslated Regions (genetics, immunology)
  • Acquired Immunodeficiency Syndrome (epidemiology, genetics, immunology, metabolism)
  • Alleles
  • Asian People
  • CD8-Positive T-Lymphocytes (immunology, metabolism)
  • China (epidemiology)
  • DNA, Viral (genetics, immunology, metabolism)
  • Female
  • Gene Expression Regulation (genetics, immunology)
  • HIV-1 (genetics, immunology, metabolism)
  • HLA-C Antigens (biosynthesis, genetics, immunology)
  • Humans
  • Interferon-gamma (genetics, immunology, metabolism)
  • Male
  • Mutation
  • Polymorphism, Genetic
  • Proviruses (genetics, immunology, metabolism)
  • Retrospective Studies

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