Polymorphisms in TLR2 and TLR7 are associated with plasma HIV-1 RNA set-point in an African heterosexual cohort

Abstract

Background: The Toll-like receptor (TLR) genes mediate the innate response to viral infections and may impact HIV-1 pathogenesis. We evaluated TLR polymorphisms for association with plasma HIV-1 RNA set-point in HIV-1 infected individuals from East and Southern Africa. Methods: Analyses included prospective data and DNA from 500 Africans with heterosexually-acquired HIV-1 (125 incident, 375 prevalent). For incident HIV-1, set-point was defined as the median plasma HIV-1 RNA level >4 months after the estimated infection date. For prevalent HIV-1, set-point was the average of >2 consecutive plasma HIV-1 RNA measurements before ART initiation or CD4 decline to<200 cells/mm3. Genotyping was performed for 124 single nucleotide polymorphisms (SNPs) from 6 TLR and 2 TLRassociated signaling genes (TIRAP and MYD88) and 144 ancestral informative markers. These included 8 candidate SNPs previously associated with HIV-1, and 115 haplotype tagging SNPs (tagSNPs) representing common variation across TLR genes. Associations were determined using linear regression with adjustment for sex, age, and population stratification, and Bonferroni correction. Results: Among 492 HIV-1 infected individuals who passed quality control, the median HIV-1 set-point was 4.6 (IQR: 3.8-5.0) log10 copies/mL and did not differ between seroprevalent and seroincident participants. TLR2-rs3804100 (minor allele frequency [MAF]=0.053), a candidate C-T synonymous SNP located in exon 1 was associated with an average 0.37 (95% confidence interval [CI]: 0.10, 0.65, p=0.007) log10 copies/mul increased set-point. TLR7- rs179012, a haplotype-tagging SNP located in intron 1 was associated with a 0.31 (95% CI: 0.47, 0.14, Bonferroni-adjusted p=0.032) log10 copies/mul decrease in HIV-1 set-point. Conclusion: These are the first associations between TLR polymorphisms and plasma HIV-1 RNA level reported among African populations. TLR2 rs3804100 has been previously linked with more rapid disease progression in Caucasians. Our finding of TLR7 rs179012and improved control of infection has not been previously reported. Further study of these SNPs may improve understanding of HIV-1 pathogenesis.