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

Beima-Sofie, Kristin M.a,e; Bigham, Abigail W.h; Lingappa, Jairam R.c,e,f; Wamalwa, Daltonj; Mackelprang, Romel D.e; Bamshad, Michael J.f,g; Maleche-Obimbo, Elizabethj; Richardson, Barbra A.d,e,i; John-Stewart, Grace C.b,c,e,d

doi: 10.1097/QAD.0b013e3283629117
Epidemiology and Social

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 log10 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.

aInstitute for Public Health Genetics

bDepartment of Epidemiology

cDepartment of Medicine

dDepartment of Biostatistics

eDepartment of Global Health

fDepartment of Pediatrics

gDepartment of Genome Sciences, University of Washington, Seattle, Washington

hDepartment of Anthropology, University of Michigan, Ann Arbor, Michigan

iVaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA

jDepartment of Paediatrics, University of Nairobi, Nairobi, Kenya.

Correspondence to Kristin Beima-Sofie, Harborview Medical Center, Box 359909, 325 Ninth Avenue, Seattle, WA 98104, USA. Tel: +1 206 897 6583; fax: +1 206 543 4818; e-mail: beimak@uw.edu

Received 1 March, 2013

Revised 22 April, 2013

Accepted 24 April, 2013

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© 2013 Lippincott Williams & Wilkins, Inc.