|dc.description.abstract||Host susceptibility to human immunodeficiency virus-1 (HIV-1) infection and
disease progression to acquired immunodeficiency syndrome (AIDS) varies
widely amongst individuals. This observation led to the identification of host
genetic factors playing a vital role in HIV-1 pathogenesis. Previous studies
mainly focusing on Caucasian-based populations have indicated possible
associations between genetic variants and host susceptibility to HIV-1/AIDS.
The limited studies performed on African-based populations have emphasised
the need for extensive investigation of both previously reported and particularly
novel genetic variants within the older and genetically diverse Sub-Saharan
In this study, the case-control samples were represented by African individuals
of Xhosa descent, all residing in the Western Cape Province of South Africa.
This included 257 HIV-1 seropositive patients and 110 population-matched
HIV-1 seronegative controls. Mutational screening was performed in a subset
of individuals for the entire coding regions of the CC chemokine receptor 5
(CCR5) and CC chemokine receptor 2 (CCR2) genes, and the 3’ untranslated
region of the CXC chemokine ligand (CXCL12) gene, as previously reported
(Petersen, 2002). Further analysis of these genes in a larger study sample
involved the genotyping of previously identified mutations and single nucleotide
polymorphisms (SNPs), which forms part of the present study. In addition,
mutational screening was performed for the entire coding region of the
CXC 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. Significant
associations were observed with HIV-1 susceptibility in the Xhosa population of
South Africa. These included the CCR5-2733A>G, CX3CR1V249I,
IL10-819C>T and IL10-592C>A SNPs being associated with a reduced risk for
HIV-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 with
reduced risk for HIV-1 infection. This included the identification of a novel IL4
haplotype restricted to the HIV-1 seronegative control group.
This study emphasises the importance of considering genetic diversity across
all populations, as certain HIV-1/AIDS associations appear to be restricted to
specific ethnic groups. These findings have also provided an understanding for
further elucidating the functional roles of genetic variants in determining
HIV-1/AIDS susceptibility. Ultimately, such genetic association studies will
contribute to establishing HIV-1/AIDS risk profiles for African-based populations
from pandemic-stricken Sub-Saharan Africa.||en_ZA