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.
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  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. 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. 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, SDF1-38 A, and CCR5 promoter genotypes 59029G/G  and P1/P1. 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. 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].
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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