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

Expression of CC chemokine receptor 5 (CCR5), the major coreceptor for HIV- 1 cell entry, and its ligands (e.g., RANTES and MIP-1 alpha) is widely rega rded as central to the pathogenesis of HIV-1 infection. By surveying nearly 3,000 HIV+ and HIV- individuals from worldwide populations for polymorphis ms in the genes encoding RANTES, MIP-1 alpha: and CCR5, we show that the ev olutionary histories of human populations have had a significant impact on the distribution of variation in these genes, and that this may be responsi ble, in part, for the heterogeneous nature of the epidemiology of the HIV-1 pandemic, The varied distribution of RANTES haplotypes (AC, GC, and AC) as sociated with population-specific HIV-I transmission- and disease-modifying effects is a striking example. Homozygosity for the AC haplotype was assoc iated with an increased risk of acquiring HIV-1 as well as accelerated dise ase progression in European Americans, but not in African Americans. Yet. t he prevalence of the ancestral AC haplotype is high in individuals of Afric an origin, but substantially lower in non-Africans. In a Japanese cohort, A G-containing RANTES haplotype pairs were associated with a delay in disease progression; however, we now show that their contribution to HIV-1 pathoge nesis and epidemiology in other parts of the world is negligible because th e AG haplotype is infrequent in non-far East Asians. Thus, the varied distr ibution of RANTES, MIP-1 alpha, and CCR5 haplotype pairs and their populati on-specific phenotypic effects on HIV-1 susceptibility and disease progress ion results in a complex pattern of biological determinants of HIV-1 epidem iology. These findings have important implications for the design, assessme nt, and implementation of effective HIV-I intervention and prevention strat egies.