Race-specific HIV-1 disease-modifying effects associated with CCR5 haplotypes

Abstract

Genetic variation in CC chemokine receptor 5 (CCR5), the major HIV-1 coreceptor, has been shown to influence HIV-1 transmission and disease progression. However, it is generally assumed that the same CCR5 genotype (or haplotype) has similar phenotypic effects in different populations. To test this assumption, we used an evolutionary-based classification of CCR5 haplotypes to determine their associated HIV-1 disease-modifying effects in a large wellcharacterized racially mixed cohort of HIV-1-seropositive individuals. We demonstrate that the spectrum of CCR5 haplotypes associated with disease acceleration or retardation differs between African Americans and Caucasians. Also, we show that there is a strong interactive effect between CCR5 haplotypes with different evolutionary histories. The striking population-specific phenotypic effects associated with CCR5 haplotypes emphasize the importance of understanding the evolutionary context in which disease susceptibility genes are expressed.

R5 HIV productively infects Langerhans cells, and infection levels are regulated by compoundCCR5polymorphisms

“…Of additional interest, HIV ϩ persons with a Ϫ2459A͞A ϩ ORF⌬32͞wt diplotype demonstrated the lowest levels of plasma viremia. Furthermore, our data linking ex vivo R5 HIV susceptibility to CCR5 genotype are also consistent with additional cohort data correlating CCR5 genotype and HIV disease progression as reported by two other studies (33,35). Thus, our current ex vivo infection findings with LCs provide a plausible biologic explanation for observed epidemiologic data obtained from large cohorts of individuals regarding host genetic susceptibility to HIV infection.…”

“…4B). As four different haplotypes have been identified that contain the Ϫ2459G allele (haplotypes A-D) and three different haplotypes have been identified that contain the Ϫ2459A allele [haplotypes E, F1, and G1; excludes haplotypes containing CCR264I (F2) and ORF⌬32 (G2) (33)], it is important to note that no single Ϫ2459G haplotype was consistently associated with a low percentage of p24 ϩ LCs and no single Ϫ2459A haplotype was consistently associated with a high percentage of p24 ϩ LCs. Although significant differences in HIV infection levels in LCs among individuals who were homozygous for the wild-type ORF with either Ϫ2459A͞A,Ϫ2459A͞G, or Ϫ2459G͞G promoter genotypes were not detected, LCs isolated from Ϫ2459G͞G individuals tended to be less susceptible to HI V than LCs isolated from Ϫ2459A͞A individuals (Ϫ2459G͞G, n ϭ 13; Ϫ2459A͞A, n ϭ 15; Mann-Whitney U test, P ϭ 0.093; Fig.…”

“…Interestingly, ORF⌬32, which is known to confer protection against HIV infection, is tightly linked to the promoter Ϫ2459A allele, known to be associated with HIV disease progression (25). Although there is a growing awareness that complex polymorphic CCR5 haplotypes are associated with slower or rapid progression to AIDS (33)(34)(35)(36), less is known about how Abbreviations: LC, Langerhans cell; DC, dendritic cell; mDC, monocyte-derived DC; DC-SIGN, DC-specific ICAM-3-grabbing nonintegrin; SNP, single-nucleotide polymorphism; AZT, 3Ј-azido-3Ј-deoxythymidine; RANTES, regulated on activation normal T cell expressed and secreted.…”

CCR5 promoter polymorphism determines macrophage CCR5 density and magnitude of HIV-1 propagation in vitro

“…Other studies have shown correlations between disease progression and the CCR2-64 I/V amino acid substitution and between CCR5 promoter haplotype/haplotype combinations (diplotype) [10,19,[23][24][25][26][27][28]. We were unable to demonstrate any relationship between these diplotypes and the in vitro phenotype; however, these additional analyses may have been limited by the small numbers of individuals in the diplotype in vitro phenotype categories observed in this study.…”

Distribution of three HIV-1 resistance-conferring polymorphisms (SDF1-3′A, CCR2-64I, and CCR5-Δ32) in global populations

“…The errors introduced by this assumption should be very small, as RH index differences between racial groups are generally small (see Table 1 in Winkler et al). 12 However, it was recently shown that the RH indices of the haplotypes containing newly identified polymorphisms in the promoter region of CCR5 [19][20][21] are higher in African Americans than they are in European Americans. 19 Therefore, the RH index in African populations in this study is likely to be underestimated and our conclusion of high RH in Africa still stands.…”