Impact of novel TRIM5alpha variants, Gly110Arg and G176del, on the anti-HIV-1 activity and the susceptibility to HIV-1 infection.
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.
Nakajima
Toshiaki
T
Department of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
Nakayama
Emi E
EE
Kaur
Gurvinder
G
Terunuma
Hiroshi
H
Mimaya
Jun-ich
JI
Ohtani
Hitoshi
H
Mehra
Narinder
N
Shioda
Tatsuo
T
Kimura
Akinori
A
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
D000090103:Antiviral Restriction Factors; D002352:Carrier Proteins; D000070584:Tripartite Motif Proteins; C477346:TRIM5 protein, human; D044767:Ubiquitin-Protein Ligases