Dominant influence of HLA-B in mediating the potential co-evolution of HIV and HLA.

Journal article

The extreme polymorphism in the human leukocyte antigen (HLA) class I region of the human genome is suggested to provide an advantage in pathogen defence mediated by CD8+ T cells. HLA class I molecules present pathogen-derived peptides on the surface of infected cells for recognition by CD8+ T cells. However, the relative contributions of HLA-A and -B alleles have not been evaluated. We performed a comprehensive analysis of the class I restricted CD8+ T-cell responses against human immunodeficiency virus (HIV-1), immune control of which is dependent upon virus-specific CD8+ T-cell activity. In 375 HIV-1-infected study subjects from southern Africa, a significantly greater number of CD8+ T-cell responses are HLA-B-restricted, compared to HLA-A (2.5-fold; P = 0.0033). Here we show that variation in viral set-point, in absolute CD4 count and, by inference, in rate of disease progression in the cohort, is strongly associated with particular HLA-B but not HLA-A allele expression (P < 0.0001 and P = 0.91, respectively). Moreover, substantially greater selection pressure is imposed on HIV-1 by HLA-B alleles than by HLA-A (4.4-fold, P = 0.0003). These data indicate that the principal focus of HIV-specific activity is at the HLA-B locus. Furthermore, HLA-B gene frequencies in the population are those likely to be most influenced by HIV disease, consistent with the observation that B alleles evolve more rapidly than A alleles. The dominant involvement of HLA-B in influencing HIV disease outcome is of specific relevance to the direction of HIV research and to vaccine design.

Authors: Kiepiela, P; Leslie, A; Honeyborne, I; Ramduth, D; Thobakgale, C

• Publication status: Published
• Journal: Nature
• Volume: 432
• Issue: 7018
• Pages: 769-775
• Publication date: 2004-12-01
• DOI: 10.1038/nature03113
• EISSN: 1476-4687
• ISSN: 0028-0836
• Language: English
• Keywords: Biological Evolution; Epitopes, T-Lymphocyte; Male; Africa, Southern; HIV-1; HLA-A Antigens; Gene Products, nef; nef Gene Products, Human Immunodeficiency Virus; Humans; HLA-B Antigens; HIV Infections; Viral Load; CD8-Positive T-Lymphocytes; Infant; Female; Gene Frequency; Polymorphism, Genetic