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

Ball, Terry Blakea; Ji, Hezhaoa; Kimani, Joshuab; McLaren, Paula; Marlin, Crystala; Hill, Adrian VSc; Plummer, Francis Allana,d

doi: 10.1097/QAD.0b013e3280ef6ae1
Basic Science

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-γ 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.

From the aDepartment of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, Manitoba, Canada

bDepartment of Microbiology, University of Nairobi, Nairobi, Kenya

cThe Wellcome Trust Centre for Human Genetics, Department of Clinical Medicine, University of Oxford, Oxford, UK

dNational Microbiology Laboratory, Canadian Science Center for Human and Animal Health, Winnipeg, Manitoba, Canada.

Received 13 September, 2006

Revised 30 December, 2006

Accepted 19 January, 2007

Correspondence to Terry Blake Ball, Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Room 507, Basic Medical Science Building, 730 William Avenue, Winnipeg, Manitoba, Canada R3E0W3. Tel: +1 204 789 3202; e-mail: tball@cc.umanitoba.ca

© 2007 Lippincott Williams & Wilkins, Inc.