Global survey of genetic variation in CCR5 , RANTES , and MIP-1 α: Impact on the epidemiology of the HIV-1 pandemic

Abstract

Expression of CC chemokine receptor 5 (CCR5), the major coreceptor for HIV-1 cell entry, and its ligands (e.g., RANTES and MIP-1␣) is widely regarded as central to the pathogenesis of HIV-1 infection. By surveying nearly 3,000 HIV؉ and HIV؊ individuals from worldwide populations for polymorphisms in the genes encoding RANTES, MIP-1␣, and CCR5, we show that the evolutionary histories of human populations have had a significant impact on the distribution of variation in these genes, and that this may be responsible, in part, for the heterogeneous nature of the epidemiology of the HIV-1 pandemic. The varied distribution of RANTES haplotypes (AC, GC, and AG) associated with population-specific HIV-1 transmission-and diseasemodifying effects is a striking example. Homozygosity for the AC haplotype was associated with an increased risk of acquiring HIV-1 as well as accelerated disease progression in European Americans, but not in African Americans. Yet, the prevalence of the ancestral AC haplotype is high in individuals of African origin, but substantially lower in non-Africans. In a Japanese cohort, AG-containing RANTES haplotype pairs were associated with a delay in disease progression; however, we now show that their contribution to HIV-1 pathogenesis and epidemiology in other parts of the world is negligible because the AG haplotype is infrequent in non-Far East Asians. Thus, the varied distribution of RANTES, MIP-1␣, and CCR5 haplotype pairs and their population-specific phenotypic effects on HIV-1 susceptibility and disease progression results in a complex pattern of biological determinants of HIV-1 epidemiology. These findings have important implications for the design, assessment, and implementation of effective HIV-1 intervention and prevention strategies.

Global human genetics of HIV-1 infection and China

“…The -403A-28G haplotype was shown to be associated with delayed disease progression in HIV-1 infected Japanese, but exerts no influence on the incidence of HIV-1 infection [52]. In European-Americans, the compound genotype -403G/A -28C/C was reported to be resistant to AIDS progression in one study [53], but not in another [54]. These RANTES polymorphisms have no effect on HIV-1 infection and disease progression in African-Americans [54].…”

“…In European-Americans, the compound genotype -403G/A -28C/C was reported to be resistant to AIDS progression in one study [53], but not in another [54]. These RANTES polymorphisms have no effect on HIV-1 infection and disease progression in African-Americans [54]. Most recently, An et al have found that 3 SNPs (-403A in the promoter, In1.1C in the first intron, and 3'222C in the 3' untranslated region) are associated with increased frequency of HIV-1 infection, and that the In1.1C allele or haplotypes display a strong association with rapid progression to AIDS among HIV-1 infected African-Americans and European-Americans [108].…”

“…Significant studies in the past few years have also demonstrated that innate immunity including genetic polymorphisms in host genes can affect the risk for HIV-1 infection and disease progression (Tab. 1), although the effect of these alleles has been inconsistent [32,[45][46][47][48][49][50][51][52][53][54][55] (reviewed in [56]). Here, we review global and Chinese studies on human genetic polymorphisms and their association with HIV-1 infection.…”

“…individuals that are CCR5-32 homozygotes (people who inherited the CCR5-32 from both parents) are resistant to HIV-1 infection, indicating that genotype CCR5-32 is highly protective against HIV-1 infection [45][46][47][48][49][50]54]. However, this protection is not absolute because rare individuals homozygous for CCR5-32 are infected with HIV-1 strains that may utilize another co-receptor, such as CXCR4 [64][65][66][67][68].…”

“…However, this protection is not absolute because rare individuals homozygous for CCR5-32 are infected with HIV-1 strains that may utilize another co-receptor, such as CXCR4 [64][65][66][67][68]. Furthermore, homozygous CCR5-32 is found only in 1% of the general population of Caucasians, but not in Africans, Asians or other ethnic groups [45][46][47][48][49][50]54], and the majority of highly exposed yet uninfected individuals have two normal CCR5 alleles (called wild-type, or wt). Similarly, we found CCR5-32 homozygotes in 1.0% (7 out of 705) of HIV-1 seronegative individuals and 3.1% (3 out of 97) of ES.…”