High Frequency of HIV Mutations Associated with HLA-C Suggests Enhanced HLA-C–Restricted CTL Selective Pressure Associated with an AIDS-Protective Polymorphism

• Published in: The Journal of immunology (1950) Vol. 188; no. 9; pp. 4663 - 4670
• Main Authors: Blais, Marie-Eve, Zhang, Yonghong, Rostron, Tim, Griffin, Harry, Taylor, Stephen, Xu, Keyi, Yan, Huiping, Wu, Hao, James, Ian, John, Mina, Dong, Tao, Rowland-Jones, Sarah L
• Format: Journal Article
• Language: English
• Published: England 01.05.2012
• Subjects: 3' Untranslated Regions - genetics; 3' Untranslated Regions - immunology; Acquired Immunodeficiency Syndrome - epidemiology; Acquired Immunodeficiency Syndrome - genetics; Acquired Immunodeficiency Syndrome - immunology; Acquired Immunodeficiency Syndrome - metabolism; Alleles; Asian People; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; China - epidemiology; DNA, Viral - genetics; DNA, Viral - immunology; DNA, Viral - metabolism; Female; Gene Expression Regulation - genetics; Gene Expression Regulation - immunology; HIV-1 - genetics; HIV-1 - immunology; HIV-1 - metabolism; HLA-C Antigens - biosynthesis; HLA-C Antigens - genetics; HLA-C Antigens - immunology; Human immunodeficiency virus 1; Humans; Interferon-gamma - genetics; Interferon-gamma - immunology; Interferon-gamma - metabolism; Male; Mutation; Polymorphism, Genetic; Proviruses - genetics; Proviruses - immunology; Proviruses - metabolism; Retrospective Studies; China
• DOI: 10.4049/jimmunol.1103472
• ISSN: 0022-1767; 1550-6606

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.