title: Dominant influence of HLA-B in mediating the potential co-evolution of HIV and HLA.
abstract: 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.affiliation: HIV Pathogenesis Programme, The Doris Duke Medical Research Institute, University of KwaZuluNatal, 719 Umbilo Road, Durban 4015, South Africa.
authors.forename: Photini
authors.initials: P
authors.lastname: Kiepiela
authors.forename: Alasdair J
authors.initials: AJ
authors.lastname: Leslie
authors.forename: Isobella
authors.initials: I
authors.lastname: Honeyborne
authors.forename: Danni
authors.initials: D
authors.lastname: Ramduth
authors.forename: Christina
authors.initials: C
authors.lastname: Thobakgale
authors.forename: Senica
authors.initials: S
authors.lastname: Chetty
authors.forename: Prinisha
authors.initials: P
authors.lastname: Rathnavalu
authors.forename: Corey
authors.initials: C
authors.lastname: Moore
authors.forename: Katja J
authors.initials: KJ
authors.lastname: Pfafferott
authors.forename: Louise
authors.initials: L
authors.lastname: Hilton
authors.forename: Peter
authors.initials: P
authors.lastname: Zimbwa
authors.forename: Sarah
authors.initials: S
authors.lastname: Moore
authors.forename: Todd
authors.initials: T
authors.lastname: Allen
authors.forename: Christian
authors.initials: C
authors.lastname: Brander
authors.forename: Marylyn M
authors.initials: MM
authors.lastname: Addo
authors.forename: Marcus
authors.initials: M
authors.lastname: Altfeld
authors.forename: Ian
authors.initials: I
authors.lastname: James
authors.forename: Simon
authors.initials: S
authors.lastname: Mallal
authors.forename: Michael
authors.initials: M
authors.lastname: Bunce
authors.forename: Linda D
authors.initials: LD
authors.lastname: Barber
authors.forename: James
authors.initials: J
authors.lastname: Szinger
authors.forename: Cheryl
authors.initials: C
authors.lastname: Day
authors.forename: Paul
authors.initials: P
authors.lastname: Klenerman
authors.forename: James
authors.initials: J
authors.lastname: Mullins
authors.forename: Bette
authors.initials: B
authors.lastname: Korber
authors.forename: Hoosen M
authors.initials: HM
authors.lastname: Coovadia
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Walker
authors.forename: Philip J R
authors.initials: PJ
authors.lastname: Goulder
mesh_terms: D000353:Africa, Southern; D005075:Biological Evolution; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D005787:Gene Frequency; D015693:Gene Products, nef / Q000737:chemistry; D015658:HIV Infections / Q000276:immunology* / Q000821:virology*; D015497:HIV-1 / Q000235:genetics / Q000276:immunology* / Q000502:physiology*; D015234:HLA-A Antigens / Q000235:genetics / Q000276:immunology; D015235:HLA-B Antigens / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007223:Infant; D008297:Male; D011110:Polymorphism, Genetic / Q000235:genetics; D019562:Viral Load; D054311:nef Gene Products, Human Immunodeficiency Virus
chemical_list: D018984:Epitopes, T-Lymphocyte; D015693:Gene Products, nef; D015234:HLA-A Antigens; D015235:HLA-B Antigens; D054311:nef Gene Products, Human Immunodeficiency Virus