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HLA-B*5703 independently associated with slower HIV-1 disease progression in Rwandan women

Costello, Carolineab; Tang, Jianmingac; Rivers, Charlesab; Karita, Etienned; Meizen-Derr, Jareenb; Allen, Susanb; Kaslow, Richard


aProgram in Epidemiology of Infection and Immunity, School of Public Health; bDepartment of Epidemiology; and cDivision of Geographic Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA; and dNational AIDS Control Program, BP 780, Kigali, Rwanda.

Sponsorship: This work was supported in part by NIH grant AI42454.

Received: 4 March 1999; accepted: 8 June 1999.

Studies over the past decade have produced clear evidence that products of the human major histocompatibility complex (HLA) govern disease progression after HIV-1 infection[1-6]. In Caucasian populations one or more markers contained in certain class I HLA haplotypes A1-Cw7-B8 and Cw4-B35 have repeatedly been implicated as determinants of rapid progression[5-8], whereas HLA-B27 and B57 have consistently shown association with slow progression[1,6,9].

In experimental studies [10,11] B*5701-restricted cytotoxic T lymphocyte (CTL) epitopes appear to be immunodominant in B*57-positive individuals with more benign infection. A number of B*57-restricted CTL epitopes have been mapped to HIV-1 Gag, Nef and reverse transcriptase genes[11,12], suggesting that HIV-specific CTL responses against key components in early viral transcription and translation are probably responsible for the delay in progression to AIDS[13].

We performed HLA genotyping for 202 HIV-1 clade A virus-infected Rwandan women using standard molecular techniques, including polymerase chain reaction with sequence-specific primers, genomic sequencing, and DNA single-strand conformation polymorphism. Consistent with the previously reported epidemiological and experimental findings on B*57 in Caucasian populations, our study in Rwandans revealed the favourable effects of HLA-B*5703 on HIV-1 disease progression: B*5703 was absent from 15 rapid progressors (AIDS in >6 years) but seen in 18 (17.8%) of 101 slow progressors (symptom-free in >10 years), and 8 (9.3%) of 86 intermediate/ indeterminant progressors (no extreme clinical outcome in 6-10 years) (proportional odds ratio=0.37, P=0.02). Certain other HLA class I markers or peptide transporter (TAP) variants previously associated with protection and frequent enough to analyse in this population were not as strongly associated with slow progression as B*5703, or their associations appeared to be due to linkage disequilibrium or coincidental occurrence with the B*57 allele. The c2 allele in tumour necrosis factor microsatellite c [14] was also excluded as a possible explanation for the B*57 relationship (J. Tang, unpublished data).

Our sequencing of HLA-B exon 2 and exon 3 revealed only B*5703 in Rwandans, but almost exclusively B*5701 in Caucasians. B*5703 differed from B*5701 by substitutions of asparagine for aspartic acid at position 114 and serine for tyrosine at position 116 in the agr;2 domain. The change of charged aspartic acid to the uncharged asparagine could potentially affect the antigen-binding sites. However, emerging data based on humans and chimpanzees with long-term non-progressing HIV-1 infection already suggested that HLA class I alleles (including B*5701 and B*2705), although differing starkly in their agr;1 and agr;2 domains, can present identical HIV-1-derived peptides for CTL response[15]. HLA class I amino acid sequences can also share structural similarities in a number of HLA allelic variants at the same locus and at different loci[16]. However, B*57 in humans has not been shown to group with other class I alleles, and data on structural homology are unavailable to demonstrate detailed peptide-binding specificity common to B*57 and other protective HLA alleles that have been recognized in various cohort studies.

HIV/AIDS-related factors outside the HLA system did not explain the protection conferred by B*5703 in the Rwandan women studied. For example, the B*5703 effect remained consistent in the presence or absence of CCR2b-64I[17], SDF1-38 A[18], and CCR5 promoter genotypes 59029G/G [19] and P1/P1[20]. CCR5-Δ32 was absent in the Rwandan subjects.

HLA-B*57 can form haplotypes with at least seven other class I antigens in Caucasian and African populations alone[21]. In Rwandans, the B*57-Cw*07 haplotype was common, whereas B*57-Cw*06 is predominant in European Caucasians; neither of the C antigens alone suggested a significant association with slower HIV-1 disease progression. Additional antigens on these haplotypes may have their own roles in mediating HIV-1 pathogenesis, but the independent association of HLA-B*57 alleles with slower disease progression in distinct HIV-1-infected populations may imply the same ‚predominant‚ effect suggested by the experimentally demonstrated patterns of B*57-restricted CTL response[10,11]. Confirmation of cross-population protection would elevate B*57 to a higher status as a vaccine ‚target‚ and urge complete and systematic identification of the spectrum of HIV-1 peptides presented by B*5701 and B*5703. In particular, the application of powerful new tools and experimental models to elucidate HLA allele-specific function at the molecular level should enhance the efforts to develop effective HIV-1 vaccines[11,22].

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The author would like to thank the staff and participants in Project San Francisco in Kigali, Rwanda. The work presented here has received additional support from the Center for AIDS Research, University of Alabama at Birmingham.

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1. Kaslow RA, Carrington M, Apple R, et al. Influence of combinations of human major histocompatibility complex genes on the course of HIV-1 infection. Nature Med 1996, 2:405-411.
2. Keet IPM, Klein MR, Just JJ, Kaslow RA. The role of host genetics in the natural history of HIV-1 infection: the needles in the haystack. AIDS 1996, 10 (Suppl. A):S59-S67.
3. Malkovsky M. HLA and natural history of HIV infection. Lancet 1996, 348:142-143.
4. Winchester R, Charron D, Louie L, et al. The role of HLA in influencing the time of development of a particular outcome of HIV-1 infection. In: HLA: Proceedings of the 12th International Histocompatibility Workshop. Charron D (editor). Paris: Medical and Scientific International Publisher; 1997. pp. 423-428.
5. Carrington M, Nelson GW, Martin MP, et al. HLA and HIV-1: heterozygosity advantage and B*35-Cw*04 disadvantage. Science 1999, 283:1748-1752.
6. Keet IPM, Tang J, Klein MR, et al. Consistent associations of HLA class I, class II and transporter (TAP) gene products with progression of human immunodeficiency virus-1 infection in homosexual men. J Infect Dis 1999, 180:299-309.
7. Steel CM, Ludlam CA, Beatson D, et al. HLA haplotype A1 B8 DR3 as a risk factor for HIV-related disease. Lancet 1988, 1:1185-1188.
8. Kaslow RA, Duquesnoy R, VanRaden M, et al. Combinations of A1, Cw7, B8, DR3 HLA antigens associated with rapid decline of T-helper lymphocytes in HIV-1 infected homosexual men: a report from the Multicenter AIDS Cohort Study. Lancet 1990, 335:927-930.
9. Klein MR, Keet IPM, D‚Amaro J, et al. Associations between HLA frequencies and pathogenic features of human immunodeficiency virus type 1 infection in seroconverters from the Amsterdam cohort of homosexual men. J Infect Dis 1994, 169:1244-1249.
10. Culmann B, Gomard E, Kieny M-P, et al. Six epitopes reacting with human cytotoxic CD8+ lymphocytes in the central region of the HIV-1 Nef protein. J Immunol 1991, 146:1560-1565.
11. Goulder PJR, Bunce M, Krausa P, et al. Novel, cross-restricted, conserved and immunodominant epitopes I. slow progressors in HIV infection. AIDS Res Hum Retroviruses 1996, 12:1691-1698.
12. Klein MR, van der Burg SH, Hovenkamp E, et al. Characterization of HLA-B57-restricted human immunodeficiency virus type 1 Gag- and RT-specific T lymphocyte responses. J Gen Virol 1998, 79:2191-2201.
13. van Baalen CA, Pontesilli O, Huisman RC, et al. Human immunodeficiency virus type 1 Rev- and Tat-specific cytotxic T lymphocyte frequencies inversely correlate with rapid progression to AIDS. J Gen Virol 1997, 78:1913-1918.
14. Khoo SH, Pepper L, Snowden N, et al. Tumor necrosis factor c2 microsatellite allele is associated with the rate of HIV disease progression. AIDS 1997, 11:423-428.
15. Balla-Jhagjhoorsingh SS, Koopman G, Mooij P, et al. Conserved CTL epitope shared between HIV-infected human long-term survivors and chimpanzees. J Immunol 1999, 162:2308-2314.
16. Cano P, Fan B, Stass S. A geometric study of the amino acid sequence of class I HLA molecules. Immunogenetics 1998, 48:324-334.
17. Smith MW, Dean M, Carrington M, et al. Contrasting genetic influence of CCR2 and CCR5 variants on HIV-1 infection and disease progression. Science 1997, 277:959-965.
18. Winkler C, Modi W, Smith MW, et al. Genetic restriction of AIDS pathogenesis by an SDF-1 chemokine gene variant. ALIVE Study, Hemophilia Growth and Development Study (HGDS), Multicenter AIDS Cohort Study (MACS), Multicenter Hemophilia Cohort Study (MHCS), San Francisco City Cohort (SFCC). Science 1998, 279:389-393.
19. McDermott DH, Zimmerman PA, Guignard F, et al. CCR5 promoter polymorphism and HIV-1 disease progression. Lancet 1998, 352:866-870.
20. Martin MP, Dean M, Smith MW, et al. Genetic acceleration of AIDS progression by a promoter variant of CCR5. Science 1998, 282:1907-1911.
21. Clayton J, Lonjou C, Whittle D. Allele and haplotype frequencies for HLA loci in various ethnic groups. In: HLA: Proceedings of the 12th International Histocompatibility Workshop. Charron D (editor). Paris: Medical and Scientific International Publisher; 1997. pp. 665-820.
22. Goulder P, Price D, Nowak M, et al. Co-evolution of human immunodeficiency virus and cytotoxic T-lymphocyte responses. Immunol Rev 1997, 159:17-29.
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