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Effects of human TRIM5alpha polymorphisms on antiretroviral function and susceptibility to human immunodeficiency virus infection |
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| Authors: | Javanbakht Hassan An Ping Gold Bert Petersen Desiree C O'Huigin Colm Nelson George W O'Brien Stephen J Kirk Gregory D Detels Roger Buchbinder Susan Donfield Sharyne Shulenin Sergey Song Byeongwoon Perron Michel J Stremlau Matthew Sodroski Joseph Dean Michael Winkler Cheryl |
| Affiliation: | a Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Division of AIDS, Harvard Medical School, Boston, MA 02115, USA b Basic Research Program, SAIC-Frederick, Laboratory of Genomic Diversity, NCI, Frederick, MD 21702, USA c Laboratory of Genomic Diversity, National Cancer Institute, Frederick, MD 21702, USA d Department of Medical Virology, University of Stellenbosch, Tygerberg Medical School, South Africa e Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA f UCLA School of Public Health, Department of Epidemiology, Center for the Health Sciences, Los Angeles, CA 90095, USA g Medicine and Epidemiology, University of California, San Francisco, CA 94143, USA h Rho, Incorporated, Chapel Hill, NC 27514, USA i Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115, USA |
| Abstract: | TRIM5α acts on several retroviruses, including human immunodeficiency virus (HIV-1), to restrict cross-species transmission. Using natural history cohorts and tissue culture systems, we examined the effect of polymorphism in human TRIM5α on HIV-1 infection. In African Americans, the frequencies of two non-coding SNP variant alleles in exon 1 and intron 1 of TRIM5 were elevated in HIV-1-infected persons compared with uninfected subjects. By contrast, the frequency of the variant allele encoding TRIM5α 136Q was relatively elevated in uninfected individuals, suggesting a possible protective effect. TRIM5α 136Q protein exhibited slightly better anti-HIV-1 activity in tissue culture than the TRIM5α R136 protein. The 43Y variant of TRIM5α was less efficient than the H43 variant at restricting HIV-1 and murine leukemia virus infections in cultured cells. The ancestral TRIM5 haplotype specifying no observed variant alleles appeared to be protective against infection, and the corresponding wild-type protein partially restricted HIV-1 replication in vitro. A single logistic regression model with a permutation test indicated the global corrected P value of < 0.05 for both SNPs and haplotypes. Thus, polymorphism in human TRIM5 may influence susceptibility to HIV-1 infection, a possibility that merits additional evaluation in independent cohorts. |
| Keywords: | TRIM5α Single nucleotide polymorphism HIV-1 HIV infections Disease susceptibility Genetics Haplotype |
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