Genetic aspects of HIV-1 risk in an African setting

[摘要] Host susceptibility to human immunodeficiency virus-1 (HIV-1) infection anddisease progression to acquired immunodeficiency syndrome (AIDS) varieswidely amongst individuals. This observation led to the identification of hostgenetic factors playing a vital role in HIV-1 pathogenesis. Previous studiesmainly focusing on Caucasian-based populations have indicated possibleassociations between genetic variants and host susceptibility to HIV-1/AIDS.The limited studies performed on African-based populations have emphasisedthe need for extensive investigation of both previously reported and particularlynovel genetic variants within the older and genetically diverse Sub-SaharanAfrican populations.In this study, the case-control samples were represented by African individualsof Xhosa descent, all residing in the Western Cape Province of South Africa.This included 257 HIV-1 seropositive patients and 110 population-matchedHIV-1 seronegative controls. Mutational screening was performed in a subsetof individuals for the entire coding regions of the CC chemokine receptor 5(CCR5) and CC chemokine receptor 2 (CCR2) genes, and the 3' untranslatedregion of the CXC chemokine ligand (CXCL12) gene, as previously reported(Petersen, 2002). Further analysis of these genes in a larger study sampleinvolved the genotyping of previously identified mutations and single nucleotidepolymorphisms (SNPs), which forms part of the present study. In addition,mutational screening was performed for the entire coding region of theCXC chemokine receptor 4 (CXCR4) gene, partial coding region of the mannose binding lectin (MBL) gene, and the promoter regions of interleukin 4(IL4), interleukin 10 (IL10) and the solute carrier 11A1 (SLC11A1) genes.This was followed by genotyping of SNPs occurring in CCR5, CCR2, CXCL12,MBL, IL4, IL10, CX3C chemokine receptor 1 (CX3CR1), CC chemokine ligand 5(CCL5) and tumour necrosis factor alpha (TNFα) genes. Significantassociations were observed with HIV-1 susceptibility in the Xhosa population ofSouth Africa. These included the CCR5-2733A>G, CX3CR1V249I,IL10-819C>T and IL10-592C>A SNPs being associated with a reduced risk forHIV-1 infection, while the CCR5-2135C>T and SDF1-3'G>A (CXCL12-3'G>A)SNPs were associated with increased susceptibility to HIV-1 infection.Furthermore, certain haplotypes for IL4 and IL10 showed association withreduced risk for HIV-1 infection. This included the identification of a novel IL4haplotype restricted to the HIV-1 seronegative control group.This study emphasises the importance of considering genetic diversity acrossall populations, as certain HIV-1/AIDS associations appear to be restricted tospecific ethnic groups. These findings have also provided an understanding forfurther elucidating the functional roles of genetic variants in determiningHIV-1/AIDS susceptibility. Ultimately, such genetic association studies willcontribute to establishing HIV-1/AIDS risk profiles for African-based populationsfrom pandemic-stricken Sub-Saharan Africa.

[发布机构] Stellenbosch University