Toll-like receptor variants are associated with infant HIV-1 acquisition and peak plasma HIV-1 RNA level

摘要

Objective: We evaluated the association of single nucleotide polymorphisms (SNPs) in TLRs with infant HIV-1 acquisition and viral control. Design: Infant HIV-1 outcomes were assessed in a Kenyan perinatal HIV-1 cohort. Methods: Infants were genotyped for six candidate and 118 haplotype-tagging polymorphisms in TLRs 2, 3, 4, 7, 8, and 9, MYD88 and TIRAP. Cox proportional hazards and linear regression were performed to assess associations with time to HIV-1 acquisition, time to infant mortality, and peak viral load. Results: Among 368 infants, 56 (15%) acquired HIV-1 by month 1 and 17 (4.6%) between 1 and 12 months. Infants with the TLR9 1635A (rs352140) variant were more likely to acquire HIV-1 by 1 month [hazard ratio=1.81, 95% confidence interval (CI)=1.05-3.14, P=0.033] and by 12 months (hazard ratio=1.62, CI=1.01-2.60, P=0.044) in dominant models adjusted for maternal plasma HIV-1 RNA level and genetic ancestry. Among 56 infants infected at 1 month of age or less, at least one copy of the TLR9 1635A allele was associated with a 0.58 log10 copies/ml lower peak viral load (P=0.002). Female infants with at least one copy of the TLR8 1G (rs3764880) variant had a 0.78 log10 copies/ml higher peak viral load (P=0.0009) and having at least one copy of the C allele for a haplotype tagging TLR7 variant (rs1634319) was associated with a 0.80 log 10 copies/ml higher peak viral load in female infants (P=0.0003). Conclusion: In this African perinatal cohort, we found several TLR polymorphisms associated with HIV-1 acquisition and progression. Defining mechanisms for these TLR associations may inform HIV-1 prevention strategies that leverage innate responses.