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Journal of Virology, March 2006, p. 2463-2471, Vol. 80, No. 5
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.5.2463-2471.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Genetic Association of the Antiviral Restriction Factor TRIM5{alpha} with Human Immunodeficiency Virus Type 1 Infection

Emily C. Speelmon,1,2,3 Devon Livingston-Rosanoff,3 Shuying Sue Li,4 Quyen Vu,3 John Bui,3 Daniel E. Geraghty,3 Lue Ping Zhao,4 and M. Juliana McElrath3,5,6*

Medical Scientist Training Program,1 Molecular and Cellular Biology Program, University of Washington, Seattle, Washington,2 Clinical Research,3 Public Health Sciences Divisions, Fred Hutchinson Cancer Research Center, Seattle, Washington,4 Departments of Medicine,5 Laboratory Medicine, University of Washington School of Medicine, Seattle, Washington6

Received 20 July 2005/ Accepted 2 December 2005

The innate antiviral factor TRIM5{alpha} restricts the replication of some retroviruses through its interaction with the viral capsid protein, leading to abortive infection. While overexpression of human TRIM5{alpha} 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 TRIM5{alpha} nonsynonymous mutations on the in vitro HIV-1 susceptibility of CD4+ T cells. Therefore, any effect of TRIM5{alpha} polymorphism on HIV-1 infection in primary lymphocytes may depend on combinations of SNPs or on DNA sequences in linkage disequilibrium with the TRIM5{alpha} coding sequence.

* Corresponding author. Mailing address: Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N, D3-100, Seattle, WA 98109-1024. Phone: (206) 667-6704. Fax: (206) 667-4411. E-mail: jmcelrat{at}fhcrc.org.

Journal of Virology, March 2006, p. 2463-2471, Vol. 80, No. 5
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.5.2463-2471.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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  • Ohkura, S., Yap, M. W., Sheldon, T., Stoye, J. P. (2006). All Three Variable Regions of the TRIM5{alpha} B30.2 Domain Can Contribute to the Specificity of Retrovirus Restriction.. J. Virol. 80: 8554-8565 [Abstract] [Full Text]  
  • Emerman, M. (2006). How TRIM5{alpha} defends against retroviral invasions. Proc. Natl. Acad. Sci. USA 103: 5249-5250 [Full Text]  


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