title: Toll-like receptor variants are associated with infant HIV-1 acquisition and peak plasma HIV-1 RNA level.
abstract: OBJECTIVE
  We evaluated the association of single nucleotide polymorphisms (SNPs) in TLRs with infant HIV-1 acquisition and viral control.
  
  
  METHODS
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: 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.
authors.forename: Kristin M
authors.initials: KM
authors.lastname: Beima-Sofie
authors.forename: Abigail W
authors.initials: AW
authors.lastname: Bigham
authors.forename: Jairam R
authors.initials: JR
authors.lastname: Lingappa
authors.forename: Dalton
authors.initials: D
authors.lastname: Wamalwa
authors.forename: Romel D
authors.initials: RD
authors.lastname: Mackelprang
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bamshad
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Maleche-Obimbo
authors.forename: Barbra A
authors.initials: BA
authors.lastname: Richardson
authors.forename: Grace C
authors.initials: GC
authors.lastname: John-Stewart
mesh_terms: D018450:Disease Progression; D005260:Female; D015658:HIV Infections / Q000097:blood / Q000235:genetics* / Q000401:mortality; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007630:Kenya / Q000453:epidemiology; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012367:RNA, Viral / Q000097:blood / Q000235:genetics*; D012737:Sex Factors; D013997:Time Factors; D051193:Toll-Like Receptors / Q000235:genetics*; D019562:Viral Load / Q000235:genetics*
chemical_list: D012367:RNA, Viral; D051193:Toll-Like Receptors
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