A Candidate Gene Study of the Association of TLR4 Polymorphisms rs4986790 and rs4986791 with HIV Disease Progression and Response to HAART Treatment in Men
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Background. Host genetic factors have been shown to be associated with the diversity in the HIV/AIDS disease progression. In addition, lipopolysaccharides (LPSs) are recognized by Toll-Like Receptor 4 (TLR4), and are associated with the HIV viral load in macrophages. Furthermore, TLR4 polymorphisms rs4986790 and rs4986791 have been shown to be associated with the HIV viral setpoint. Together, these findings suggest that these TLR4 polymorphisms are associated with HIV disease progression. Objective. We studied the association of the TLR4 polymorphisms rs4986790 and rs4986791 with HIV viral setpoint, and the virologic and immunological responses to HAART treatment. Methods. We designed both cross-sectional and prospective components of this cohort study to utilize men enrolled in the Multicenter AIDS Cohort Study (MACS) who had been genotyped for single nucleotide polymorphisms (SNPs) in the TLR4 region. We applied linear regression to model the HIV viral setpoint, and log-binomial regression as well as Poisson regression with robust estimation of variance to model the virologic and immunological responses to HAART. Results. The results suggest that the two TLR4 SNPs have protective effects in terms of decreased HIV setpoint in a recessive model. The mean log10 HIV viral setpoint among men with rs4986791-TT was 0.11 lower than that among men with at least one C allele, and the mean log10 HIV setpoint among men with rs4986790-GG was 0.30 lower than that among men with at least one A allele. For the virologic response to HAART, we found that the probability of achieving an undetectable HIV RNA level within two years of HAART initiation was 47% higher among men with rs4986791-TT compared to men with at least one C at rs4986791 adjusting for cofactors, while the probability of achieving an undetectable HIV RNA level within two years of HAART initiation was 40% higher among men with rs4986790-GG compared to men with at least one A at rs4986790 adjusting for cofactors. In contrast, the two TLR4 SNPs were not associated with the immunological response of achieving 100 cells/microliters increase in CD4+ T cells within two years following HAART treatment. Conclusions. The results from this study are in accordance with previous findings that rs4986790 and rs4986791 were associated with HIV viral load, and they extended that observation by suggesting that TLR4 genotype might also be associated with achieving undetectable viral load after HAART treatment. This novel observation needs to be confirmed in other cohorts.