title: 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.
authors.affiliation: Nuffield Department of Medicine, John Radcliffe Hospital, Oxford OX3 9DS, United Kingdom.
authors.forename: Marie-Eve
authors.initials: ME
authors.lastname: Blais
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Zhang
authors.forename: Tim
authors.initials: T
authors.lastname: Rostron
authors.forename: Harry
authors.initials: H
authors.lastname: Griffin
authors.forename: Stephen
authors.initials: S
authors.lastname: Taylor
authors.forename: Keyi
authors.initials: K
authors.lastname: Xu
authors.forename: Huiping
authors.initials: H
authors.lastname: Yan
authors.forename: Hao
authors.initials: H
authors.lastname: Wu
authors.forename: Ian
authors.initials: I
authors.lastname: James
authors.forename: Mina
authors.initials: M
authors.lastname: John
authors.forename: Tao
authors.initials: T
authors.lastname: Dong
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Rowland-Jones
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics / Q000276:immunology; D000163:Acquired Immunodeficiency Syndrome / Q000453:epidemiology / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D000483:Alleles; D044466:Asian People; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002681:China / Q000453:epidemiology; D004279:DNA, Viral / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology; D015497:HIV-1 / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D015236:HLA-C Antigens / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008297:Male; D009154:Mutation; D011110:Polymorphism, Genetic; D011533:Proviruses / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D012189:Retrospective Studies
chemical_list: D020413:3' Untranslated Regions; D004279:DNA, Viral; D015236:HLA-C Antigens; D007371:Interferon-gamma