title: Genetic variants in the host restriction factor APOBEC3G are associated with HIV-1-related disease progression and central nervous system impairment in children.
abstract: BACKGROUND
  Apolipoprotein B mRNA editing catalytic polypeptide 3G (APOBEC3G) protein is incorporated into nascent virus particles and mediates cytidine deamination (C-to-U) of first-strand reverse transcripts of HIV-1 in target cells resulting in G-to-A hypermutation of the coding strand and premature degradation. We investigated the effects of APOBEC3G genetic variants on HIV-1-related disease in children.
  
  
  METHODS
  APOBEC3G variants were detected using real-time polymerase chain reaction in HIV-1-infected children from Pediatric AIDS Clinical Trials Group (PACTG) protocols P152 and P300 that evaluated the effectiveness of 3 mono- or dual-nucleoside reverse transcriptase inhibitor treatments.
  
  
  RESULTS
  Of the 1049 children evaluated, 60% were non-Hispanic black, 26% Hispanic, 13% non-Hispanic white, and 1% other or unknown race/ethnicity. Age ranged from 42 days to 18 years; 45% were males. APOBEC3G-H186R homozygous G/G genotype was associated with more rapid HIV-1 disease progression [hazard ratio (HR): 1.69; P = 0.01] and central nervous system (CNS) impairment (HR: 2.00; P = 0.02) compared with the wild-type A/A or heterozygous A/G genotype in a recessive model. In both additive and dominant models, APOBEC3G-F119F-C allele was associated with protection against disease progression (HR [additive]: 0.69; P = 0.002 and HR [dominant]: 0.60; P = 0.001, respectively) and CNS impairment (HR [additive]: 0.65; P = 0.02 and HR [dominant]: 0.54; P = 0.007, respectively). These associations remained significant in multivariate analyses controlling for baseline characteristics or previously identified genetic variants known to alter HIV-1-related disease in this cohort of children.
  
  
  CONCLUSIONS
  APOBEC3G-H186R and F119F variants are associated with altered HIV-1-related disease progression and CNS impairment in children.
authors.affiliation: Department of Pediatrics, Division of Infectious Diseases, University of California San Diego, La Jolla, CA 92093-0672, USA. kusingh@ucsd.edu
authors.forename: Kumud K
authors.initials: KK
authors.lastname: Singh
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.forename: Kathryn P
authors.initials: KP
authors.lastname: Gray
authors.forename: Mona
authors.initials: M
authors.lastname: Farhad
authors.forename: Sean
authors.initials: S
authors.lastname: Brummel
authors.forename: Terence
authors.initials: T
authors.lastname: Fenton
authors.forename: Rodney
authors.initials: R
authors.lastname: Trout
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Spector
mesh_terms: D000071480:APOBEC-3G Deaminase; D000293:Adolescent; D002493:Central Nervous System Diseases / Q000235:genetics* / Q000821:virology; D002648:Child; D002675:Child, Preschool; D003564:Cytidine Deaminase / Q000235:genetics*; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000150:complications / Q000235:genetics*; D015497:HIV-1; D006801:Humans; D007223:Infant; D053208:Kaplan-Meier Estimate; D008297:Male; D015999:Multivariate Analysis; D020641:Polymorphism, Single Nucleotide
chemical_list: D000071480:APOBEC-3G Deaminase; C464924:APOBEC3G protein, human; D003564:Cytidine Deaminase