The role of interleukin-10 promoter polymorphisms in HIV-1 susceptibility and primary HIV-1 pathogenesis.
Host genetic factors may partially account for the uneven distribution of HIV infection worldwide. In addition to influencing relative susceptibility to HIV, host genetic factors may also affect the rate of disease progression in persons who are already HIV infected. J.L-10 was previously identified as an AIDS restricting gene (ARG), i.e. human genes with polymorphic variants that influence the outcome of HIV-1 exposure or infection. IL-10 is a Th2 cytokine, with anti-inflammatory properties, and plays a significant role in the regulation of immune responses; this cytokine may also directly influence viral replication. This study focused on the role of genetic polymorphisms in the proximal promoter region of the IL-10 gene on HIV-:eptibility and primary HIV-1 pathogenesis in a South African comprising of women at high risk of HIV-1 infection In this study 228 black females from the CAPRISA Acute Infection cohort were genotyped for two polymorphisms that naturally occur within the proximal region of the IL-10 promoter, at positions -.1082 and -592 (tracking -819) relative to the transcription start site. DNA samples from study participants were genotyped using the amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) method, which utilises specifically designed primers to detect single nucleotide polymorphisms. The allele frequencies for the mutant -1082G and -592A variants were 0.3203 and 0.333 respectively.Individuals homozygous for the mutation at the -392 position (AA genotype) were 2.78 times more likely to become HIV infected, compared to those who were homozygous wild type (CC genotype) at the same position (p-value=0.0237). Among those who became HIV infected, we found a hierarchical association between IL-10 promoter variants and HIV-1 plasma viral load or CD4+ T cell counts over the course year of HIV-1 infection. At earlier time points, i.e. 0-3 months post-te -1082GG group had significantly higher median viral loads than the -AA or -1082AG groups (pvalues= <0.0001 and 0.0003 respectively); and the -1082AA group had the highest median CD4'' T cell count compared to the -1082AG or -1082GG groups and this was significant (p-values= 0.0194 and 0.0122 respectively). At 6-12 months post-infection the median viral load of the -1082GG group was lower than -1082AA group, however this was not significant (p-value=0.6767). Analysis of the effect of the -592 polymorphism showed that the -592AA group had a lower median viral load at 0-3 months post-infection compared to the homozygous wild-type group (i.e. -592CC p~value=0.0093); and the median CD4+ T cell count for the -592AA group was significantly higher than the -592CC group (p~ value= 0.0198). At 6-12 months post-infection, the median viral load as well as the median CD4+ T cell count of the -592 A A group were both no longer significantly different to the -592CC group (p-values= 0.644land 0.6461 respectively). Plasma IL-10 expression was not significantly different between the IL-I0 genotypes for any of the polymorphic positions.Overall, these results suggest that polymorphisms within the IL-10 promoter may influence the risk of HIV infection and that they may affect primary HIV-1 pathogenesis. Interestingly, our data suggests that the effect of these polymorphic variants on viral and CD4+ T cell counts may vary according to time post-infection. To our knowledge, this is the first study to suggest that an ARG may have a differential effect on markers of disease progression depending on the phase of infection studied. The mechanisms underlying these observations require further studies and may have important implications for HIV/AIDS pathogenesis and the development of effective vaccine and immunotherapeutic strategies.