TRIM5a has species-specific restriction activity against replication of many retroviruses, including HIV-1. Most primates express TRIM5a protein so that they can not be infected by HIV-1. Though human also express TRIM5a protein, it is less potent in suppressing infection of HIV-1 than most orthologs of other nonhuman primates. Previous studies suggested that polymorphisms in human TRIM5a gene might influence HIV-1 susceptibility and AIDS progress, but the potential role of human TRIM5a nucleotide variants on HIV-1 susceptibility and AIDS progress was not consistent among different population. Because there were lack of consistent conclusion about TRIM5a gene polymorphism and study among Chinese population, we perform an association study between TRIM5a polymorphism and HIV-1 infection among Chinese Intravenous Drug Users (IDUs). We resequenced TRIM5 exon2 and exon8 coding region from genomic DNA of 1523 IDUs, who are all recruited from Yunnan Province. Though we identified a total of 13 different nucleotide variants, only 4 single nucleotide polymorphisms (SNPs) were not observed at low frequencies [minor allele frequency (MAF) > 0.05]. We observed that the frequency of 43Y homozygote in seronegative IDUs was significantly higher than that in the HIV-1 infected IDUs, and the stratified analysis of H43Y SNP between Han and Dai ethnicity again confirmed the significant difference, which suggested H43Y might account for the HIV-1 resistance due to TRIM5a gene in Chinese IDUs. We performed in vitro experiment to assay the contribution of H43Y and two novel rare gene variants R97C and G110R in the TRIM5a protein to anti-HIV-1 activity. We found all 3 gene variants weakened the anti-HIV-1 activities of human TRIM5a: H43Y impairs human TRIM5a restriction of HIV-1, while R97C and G110R result in modest effects on anti-HIV-1 potency. We concluded that the effect of H43Y on HIV-1 susceptibility among Chinese IDUs might be not caused by enhanced the anti-HIV-1 activity of human TRIM5a protein, but caused by influencing immune response.
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