title: APOBEC3G expression is dysregulated in primary HIV-1 infection and polymorphic variants influence CD4+ T-cell counts and plasma viral load.
abstract: OBJECTIVE
  In the absence of HIV-1 virion infectivity factor (Vif), cellular cytosine deaminases such as apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3G (APOBEC3G) inhibit the virus by inducing hypermutations on viral DNA, among other mechanisms of action. We investigated the association of APOBEC3G mRNA levels and genetic variants on HIV-1 susceptibility, and early disease pathogenesis using viral load and CD4 T-cell counts as outcomes.
  
  
  METHODS
  Study participants were 250 South African women at high risk for HIV-1 subtype C infection. We used real-time PCR to measure the expression of APOBEC3G in HIV-negative and HIV-positive primary infection samples. APOBEC3G variants were identified by DNA re-sequencing and TaqMan genotyping.
  
  
  RESULTS
  We found no correlation between APOBEC3G expression levels and plasma viral loads (r = 0.053, P = 0.596) or CD4 T-cell counts (r = 0.030, P = 0.762) in 32 seroconverters. APOBEC3G expression levels were higher in HIV-negative individuals as compared with HIV-positive individuals (P < 0.0001), including matched pre and postinfection samples from the same individuals (n = 13, P < 0.0001). Twenty-four single nucleotide polymorphisms, including eight novel, were identified within APOBEC3G by re-sequencing and genotyping. The H186R mutation, a codon-changing variant in exon 4, and a 3' extragenic mutation (rs35228531) were associated with high viral loads (P = 0.0097 and P < 0.0001) and decreased CD4 T-cell levels (P = 0.0081 and P < 0.0001), respectively.
  
  
  CONCLUSIONS
  These data suggest that APOBEC3G transcription is rapidly downregulated upon HIV-1 infection. During primary infection, APOBEC3G expression levels in peripheral blood mononuclear cells do not correlate with viral loads or CD4 T-cell counts. Genetic variation of APOBEC3G may significantly affect early HIV-1 pathogenesis, although the mechanism remains unclear and warrants further investigation.
authors.affiliation: Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa.
authors.forename: Kavidha
authors.initials: K
authors.lastname: Reddy
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Winkler
authors.forename: Lise
authors.initials: L
authors.lastname: Werner
authors.forename: Koleka
authors.initials: K
authors.lastname: Mlisana
authors.forename: Salim S
authors.initials: SS
authors.lastname: Abdool Karim
authors.forename: Thumbi
authors.initials: T
authors.lastname: Ndung'u
mesh_terms: D000071480:APOBEC-3G Deaminase; D000328:Adult; D018791:CD4 Lymphocyte Count; D003564:Cytidine Deaminase / Q000235:genetics / Q000378:metabolism*; D018450:Disease Progression; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000097:blood / Q000276:immunology* / Q000821:virology*; D015497:HIV-1; D006801:Humans; D017354:Point Mutation / Q000235:genetics; D011110:Polymorphism, Genetic; D012333:RNA, Messenger / Q000097:blood; D019562:Viral Load; D014771:Virion / Q000235:genetics / Q000276:immunology
chemical_list: D012333:RNA, Messenger; D000071480:APOBEC-3G Deaminase; C464924:APOBEC3G protein, human; D003564:Cytidine Deaminase