Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 98, Issue 9, Pages 5199-5204Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.091056898
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Funding
- NIAID NIH HHS [AI46326, AI43279, R01 AI046326, R37 AI046326, R21 AI046326, R01 AI043279] Funding Source: Medline
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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 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 alpha: 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 AC) associated with population-specific HIV-I transmission- and disease-modifying 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 alpha, 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-I intervention and prevention strategies.
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