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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.

Original publication

DOI

10.4049/jimmunol.1103472

Type

Journal article

Journal

J Immunol

Publication Date

01/05/2012

Volume

188

Pages

4663 - 4670

Keywords

3' Untranslated Regions, Acquired Immunodeficiency Syndrome, Alleles, Asian Continental Ancestry Group, CD8-Positive T-Lymphocytes, China, DNA, Viral, Female, Gene Expression Regulation, HIV-1, HLA-C Antigens, Humans, Interferon-gamma, Male, Mutation, Polymorphism, Genetic, Proviruses, Retrospective Studies