Dominant influence of HLA-B in mediating the potential co-evolution of HIV and HLA.
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.
Kiepiela
Photini
P
HIV Pathogenesis Programme, The Doris Duke Medical Research Institute, University of KwaZuluNatal, 719 Umbilo Road, Durban 4015, South Africa.
Leslie
Alasdair J
AJ
Honeyborne
Isobella
I
Ramduth
Danni
D
Thobakgale
Christina
C
Chetty
Senica
S
Rathnavalu
Prinisha
P
Moore
Corey
C
Pfafferott
Katja J
KJ
Hilton
Louise
L
Zimbwa
Peter
P
Moore
Sarah
S
Allen
Todd
T
Brander
Christian
C
Addo
Marylyn M
MM
Altfeld
Marcus
M
James
Ian
I
Mallal
Simon
S
Bunce
Michael
M
Barber
Linda D
LD
Szinger
James
J
Day
Cheryl
C
Klenerman
Paul
P
Mullins
James
J
Korber
Bette
B
Coovadia
Hoosen M
HM
Walker
Bruce D
BD
Goulder
Philip J R
PJ
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
D018984:Epitopes, T-Lymphocyte; D015693:Gene Products, nef; D015234:HLA-A Antigens; D015235:HLA-B Antigens; D054311:nef Gene Products, Human Immunodeficiency Virus