Genetic association of the antiviral restriction factor TRIM5alpha with human immunodeficiency virus type 1 infection.
The innate antiviral factor TRIM5alpha restricts the replication of some retroviruses through its interaction with the viral capsid protein, leading to abortive infection. While overexpression of human TRIM5alpha results in modest restriction of human immunodeficiency virus type 1 (HIV-1), this inhibition is insufficient to block productive infection of human cells. We hypothesized that polymorphisms within TRIM5 may result in increased restriction of HIV-1 infection. We sequenced the TRIM5 gene (excluding exon 5) and the 4.8-kb 5' putative regulatory region in genomic DNA from 110 HIV-1-infected subjects and 96 exposed seronegative persons, along with targeted gene sequencing in a further 30 HIV-1-infected individuals. Forty-eight single nucleotide polymorphisms (SNPs), including 20 with allele frequencies of >1.0%, were identified. Among these were two synonymous and eight nonsynonymous coding polymorphisms. We observed no association between TRIM5 polymorphism in HIV-1-infected subjects and their set-point viral load after acute infection, although one TRIM5 haplotype was weakly associated with more rapid CD4(+) T-cell loss. Importantly, a TRIM5 haplotype containing the nonsynonymous SNP R136Q showed increased frequency among HIV-1-infected subjects relative to exposed seronegative persons, with an odds ratio of 5.49 (95% confidence interval = 1.83 to 16.45; P = 0.002). Nonetheless, we observed no effect of individual TRIM5alpha nonsynonymous mutations on the in vitro HIV-1 susceptibility of CD4(+) T cells. Therefore, any effect of TRIM5alpha polymorphism on HIV-1 infection in primary lymphocytes may depend on combinations of SNPs or on DNA sequences in linkage disequilibrium with the TRIM5alpha coding sequence.
Medical Scientist Training Program, Molecular and Cellular Biology Program, University of Washington, Seattle, 98109, USA.
Emily C
EC
Speelmon
Devon
D
Livingston-Rosanoff
Shuying Sue
SS
Li
Quyen
Q
Vu
John
J
Bui
Daniel E
DE
Geraghty
Lue Ping
LP
Zhao
M Juliana
MJ
McElrath
D000328:Adult; D000368:Aged; D000090103:Antiviral Restriction Factors; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000821:virology*; D002352:Carrier Proteins / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D016655:HIV Core Protein p24 / Q000032:analysis; D015658:HIV Infections / Q000235:genetics* / Q000821:virology; D015497:HIV-1 / Q000254:growth & development; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012367:RNA, Viral / Q000097:blood; D012045:Regulatory Sequences, Nucleic Acid; D017422:Sequence Analysis, DNA; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases; D019562:Viral Load
D000090103:Antiviral Restriction Factors; D002352:Carrier Proteins; D016655:HIV Core Protein p24; D012367:RNA, Viral; D000070584:Tripartite Motif Proteins; C477346:TRIM5 protein, human; D044767:Ubiquitin-Protein Ligases