HLA-A*7401-mediated control of HIV viremia is independent of its linkage disequilibrium with HLA-B*5703.

Journal article

The potential contribution of HLA-A alleles to viremic control in chronic HIV type 1 (HIV-1) infection has been relatively understudied compared with HLA-B. In these studies, we show that HLA-A*7401 is associated with favorable viremic control in extended southern African cohorts of >2100 C-clade-infected subjects. We present evidence that HLA-A*7401 operates an effect that is independent of HLA-B*5703, with which it is in linkage disequilibrium in some populations, to mediate lowered viremia. We describe a novel statistical approach to detecting additive effects between class I alleles in control of HIV-1 disease, highlighting improved viremic control in subjects with HLA-A*7401 combined with HLA-B*57. In common with HLA-B alleles that are associated with effective control of viremia, HLA-A*7401 presents highly targeted epitopes in several proteins, including Gag, Pol, Rev, and Nef, of which the Gag epitopes appear immunodominant. We identify eight novel putative HLA-A*7401-restricted epitopes, of which three have been defined to the optimal epitope. In common with HLA-B alleles linked with slow progression, viremic control through an HLA-A*7401-restricted response appears to be associated with the selection of escape mutants within Gag epitopes that reduce viral replicative capacity. These studies highlight the potentially important contribution of an HLA-A allele to immune control of HIV infection, which may have been concealed by a stronger effect mediated by an HLA-B allele with which it is in linkage disequilibrium. In addition, these studies identify a factor contributing to different HIV disease outcomes in individuals expressing HLA-B*5703.

Authors: Matthews, P; Adland, E; Listgarten, J; Leslie, A; Mkhwanazi, N

• Publication status: Published
• Journal: Journal of Immunology
• Volume: 186
• Issue: 10
• Pages: 5675-5686
• Publication date: 2011-05-01
• DOI: 10.4049/jimmunol.1003711
• EISSN: 1550-6606
• ISSN: 0022-1767
• Language: English
• Keywords: Linkage Disequilibrium; Humans; gag Gene Products, Human Immunodeficiency Virus; Molecular Sequence Data; HIV-1; Epitopes, T-Lymphocyte; CD8-Positive T-Lymphocytes; Africa; pol Gene Products, Human Immunodeficiency Virus; Alleles; HIV Infections; Viral Load; Viremia; Female; Sequence Analysis, Protein; nef Gene Products, Human Immunodeficiency Virus; HLA-B Antigens; Flow Cytometry; HLA-A Antigens; rev Gene Products, Human Immunodeficiency Virus; CD4 Lymphocyte Count