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

KM Beima-Sofie, AW Bigham, JR Lingappa… - Aids, 2013 - journals.lww.com
KM Beima-Sofie, AW Bigham, JR Lingappa, D Wamalwa, RD Mackelprang, MJ Bamshad
Aids, 2013journals.lww.com
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 …
Abstract
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 log 10 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 log 10 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.
Background
Recent studies demonstrate that innate immune responses play a critical role in HIV-1 acquisition and control [1–3]. This may be especially true in infants whose adaptive responses are still under development. Pattern recognition receptors (PRRs) are key effectors of the innate response that also bridge to adaptive immune response pathways. PRRs recognize evolutionarily conserved pathogen-associated molecular patterns (PAMPs) and PAMP recognition triggers activation of signal transduction pathways and downstream effector responses [4].
Lippincott Williams & Wilkins