Allelic variants of human beta-chemokine receptor 5 (CCR5) promoter: evolutionary relationships and predictable associations with HIV-1 disease progression

Abstract

Variability in the natural history of HIV-1 infection has been repeatedly associated with genetic variants in the betachemokine receptor 5 (CCR5) locus. While CCR5 coding sequences have demonstrated relatively limited variation, sequences of its promoter appear polymorphic in all major populations. Our studies revealed five major CCR5 promoter alleles with distributions that differed widely among the four distinct ethnic groups from Kigali, Rwanda and Bronx, New York. In particular, promoter allele P*0103 (G 59029 -T 59353 -T 59356 -A 59402 -C 59653 ) was largely restricted to black subjects. The promoter allele P*0202 (A 59029 -C 59353 -C 59356 -A 59402 -T 59653 ) was tightly linked to the slightly less frequent CCR2b-64I, a variant of the CCR2b gene, which is about 12.7 kbp upstream from the promoter region. Another closely related promoter allele P*0201 (A 59029 -C 59353 -C 59356 -A 59402 -C 59653 ) exclusively carried the far less common CCR5-⌬32, a 32-bp deletion in the CCR5 coding sequence 2 kbp downstream from the promoter. The homozygous P*0201/*0201 genotype can be predicted as a risk factor for more rapid disease progression. Among human, chimpanzee, pig-tailed macaque, and sooty mangabey promoter allelic sequences, the apparent ancestral lineage of the promoter sequence (G 59029 -T 59353 -C 59356 -A 59402 -C 59653 = human P*0102) was highly conserved across the primate species analyzed here while P*0201 and P*0202 arose more recently than the other three major alleles. Further effort to establish the mechanism by which CCR chemokine receptor polymorphisms govern the initiation and pathogenesis of primate lentivirus infection apparently requires fully detailed genotypic characterization of the affected populations.

Distribution of Chemokine ReceptorCCR2andCCR5Genotypes and Their Relative Contribution to Human Immunodeficiency Virus Type 1 (HIV-1) Seroconversion, Early HIV-1 RNA Concentration in Plasma, and Later Disease Progression

“…The prevalence of eight CCR haplotypes detected in the three cohorts ranged from 0% (D) to 37% (C) ( Table 2). Consistent with earlier studies (20,21,70), G*1 was the only haplotype with similar frequencies among Caucasians (2 to 4%) and African-Americans (3%). Haplotype D was largely restricted to AfricanAmericans, and G*2 was far less common in African-Americans than in Caucasians (P Ͻ 0.001 for both comparisons).…”

“…Distinguishing the E/E genotype from the remainder of the P1/P1 genotype combinations largely resolves the apparent discrepancy in the associations of P1/P1 with rapid progression between Caucasians (recessive) and African-Americans (dominant) (2,44). In individuals of African ancestry, higher frequencies of the non-E/E variants encompassed by P1/P1 (20,70) dilute the effect of the less frequent E/E. Thus, the E/E genotype may warrant special attention because of its relative prevalence in major ethnic groups (20,41,52).…”

“…The E/E genotype association with accelerated disease progression in Caucasians here and elsewhere (20) was predicted (70). In addition, the E/E genotype represents the major portion of an unfavorable genotype previously defined as P1/P1 (44), which is mutually exclusive of the reportedly favorable 59029G/G (ϭ303G/G here) (46).…”

“…The full extent of common CCR5 single-nucleotide polymorphisms (SNPs) and relationships among them had not been examined until recently (20,52,70). Thorough documentation of the extended CCR2 and CCR5 haplotypes has suggested that stable CCR haplotypes, alone or paired as genotypes, may influence the course of HIV-1 infection differentially according to their racial distribution (20,21,52); if so, variations in genotype frequencies among populations could have a sizeable differential impact on the course and the burden of disease (21).…”

Study of CCR5-59353C/T Polymorphism in the Iranian Patients With Chronic Hepatitis B Virus Infection

“…Therefore, the primer sequences in Table 1 were used to determine polymorphism (17); the results showed that only the last allele at the end of the reverse primer 3 was different among the 2 pairs of primers and their forward primers were similar.…”