Polymorphisms in IRF-1 associated with resistance to HIV-1 infection in highly exposed uninfected Kenyan sex workers.

Journal article

OBJECTIVE: To determine the correlation between polymorphisms in the IL-4 gene cluster and resistance to HIV-1 infection. DESIGN: : A cross-sectional genetic analysis of polymorphisms within the IL-4 gene cluster was conducted in a well-described female sex worker cohort from Nairobi, Kenya, known to exhibit differential susceptibility to HIV-1 infection. METHODS: Microsatellite genotyping was used to screen six microsatellite markers in the IL-4 gene cluster for associations with HIV-1 resistance. Further analysis of the interferon regulatory factor 1 (IRF-1) gene was conducted by genomic sequencing. Associations between IRF-1 gene polymorphisms and the HIV-1 resistance phenotype were determined using the chi-square test and Kaplan-Meier survival analysis. The functional consequence of IRF-1 polymorphism was conducted by quantitative Western blot. RESULTS: Three polymorphisms in IRF-1, located at 619, the microsatellite region and 6516 of the gene, showed associations with resistance to HIV-1 infection. The 619A, 179 at IRF-1 microsatellite and 6516G alleles were associated with the HIV-1-resistant phenotype and a reduced likelihood of seroconversion. Peripheral blood mononuclear cells from patients with protective IRF-1 genotypes exhibited significantly lower basal IRF-1 expression and reduced responsiveness to exogenous IFN-gamma stimulation. CONCLUSION: Polymorphisms in the IRF-1 gene are associated with resistance to infection by HIV-1 and a lowered level of IRF-1 protein expression. This study adds IRF-1, a transcriptional immunoregulatory gene, to the list of genetic correlates of altered susceptibility to HIV-1. This is the first report suggesting that a viral transcriptional regulator might contribute to resistance to HIV-1. Further functional analysis on the role of IRF-1 polymorphisms and HIV-1 resistance is underway.

Authors: Ball, T; Ji, H; Kimani, J; McLaren, P; Marlin, C

• Publication status: Published
• Journal: AIDS (London, England)
• Volume: 21
• Issue: 9
• Pages: 1091-1101
• Publication date: 2007-05-01
• DOI: 10.1097/qad.0b013e3280ef6ae1
• EISSN: 1473-5571
• ISSN: 0269-9370
• Language: English
• Keywords: Microsatellite Repeats; Humans; HIV-1; Interferon Regulatory Factor-1; Haplotypes; Alleles; Interferon-gamma; Polymorphism, Single Nucleotide; Genes, Viral; Female; Prostitution; Interleukin-4; HIV Infections; Cross-Sectional Studies; Genetic Predisposition to Disease; HIV Seropositivity; Polymorphism, Genetic; Gene Expression Regulation, Viral; Kenya; Genotype