title: Impact of novel TRIM5alpha variants, Gly110Arg and G176del, on the anti-HIV-1 activity and the susceptibility to HIV-1 infection.
abstract: OBJECTIVE
  TRIM5alpha is one of the factors contributing to intracellular defense mechanisms against HIV-1 infection. We investigated the association of TRIM5alpha sequence variations with the susceptibility to HIV-1 infection in Japanese and Indian.
  
  
  METHODS
  Sequence variations in TRIM5alpha were investigated in HIV-1-infected patients and ethnic-matched controls. Functional alterations caused by rare variants were analyzed.
  
  
  METHODS
  : We sequenced TRIM5alpha-exon 2 in both Japanese (94 HIV-1-infected patients and 487 controls) and Indian (101 HIV-1-infected patients and 99 controls). Frequency of variants and haplotypes were compared between the HIV-1-infected patients and controls. Functional analyses were performed for two rare variants, Gly110Arg and G176del.
  
  
  RESULTS
  The frequency of 43Tyr-allele in the Indian HIV-1-infected patients was significantly lower than that in the ethnic-matched controls (odds ratio = 0.52, 95% confidence interval = 0.31-0.89, P = 0.015). A similar tendency was observed in Japanese sample, although it was not statistically significant (odds ratio = 0.67, 95% confidence interval = 0.43-1.05, P = 0.095). On the other hand, haplotype analyses revealed that the haplotype carrying the 43Tyr-allele was significantly associated with the reduced susceptibility to HIV-1 infection in both ethnic groups. Functional analysis revealed that Gly110Arg variant weakened the anti-HIV-1 and anti-HIV-2 activities of human TRIM5alpha, whereas the truncated G176del-TRIM5 enhanced the antiviral activity of coexpressed TRIM5alpha. Epidemiological data were consistent in that Gly110Arg and G176del were associated with the susceptibility to and protection from HIV-1 infection, respectively.
  
  
  CONCLUSIONS
  Both common and rare variants of TRIM5alpha are associated with the susceptibility to HIV-1 infection.
authors.affiliation: Department of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Nakajima
authors.forename: Emi E
authors.initials: EE
authors.lastname: Nakayama
authors.forename: Gurvinder
authors.initials: G
authors.lastname: Kaur
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Terunuma
authors.forename: Jun-ich
authors.initials: JI
authors.lastname: Mimaya
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Ohtani
authors.forename: Narinder
authors.initials: N
authors.lastname: Mehra
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Shioda
authors.forename: Akinori
authors.initials: A
authors.lastname: Kimura
mesh_terms: D000090103:Antiviral Restriction Factors; D044466:Asian People / Q000235:genetics; D015153:Blotting, Western; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002352:Carrier Proteins / Q000235:genetics* / Q000276:immunology; D016022:Case-Control Studies; D018450:Disease Progression; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D015658:HIV Infections / Q000208:ethnology / Q000235:genetics* / Q000276:immunology; D015497:HIV-1 / Q000276:immunology*; D006239:Haplotypes; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases
chemical_list: D000090103:Antiviral Restriction Factors; D002352:Carrier Proteins; D000070584:Tripartite Motif Proteins; C477346:TRIM5 protein, human; D044767:Ubiquitin-Protein Ligases