Polymorphisms in IRF-1 associated with resistance to HIV-1 infection in highly exposed uninfected Kenyan sex workers.
OBJECTIVE
To determine the correlation between polymorphisms in the IL-4 gene cluster and resistance to HIV-1 infection.


METHODS
: 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.


CONCLUSIONS
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.
Ball
Terry Blake
TB
Department of Medical Microbiology and Infectious Diseases, University of Manitoba, 730 William Avenue, Winnipeg, Manitoba, Canada. tball@cc.umanitoba.ca
Ji
Hezhao
H
Kimani
Joshua
J
McLaren
Paul
P
Marlin
Crystal
C
Hill
Adrian V S
AV
Plummer
Francis Allan
FA
D000483:Alleles; D003430:Cross-Sectional Studies; D005260:Female; D015967:Gene Expression Regulation, Viral / Q000235:genetics; D005814:Genes, Viral / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D015658:HIV Infections / Q000453:epidemiology / Q000235:genetics* / Q000635:transmission; D006679:HIV Seropositivity / Q000235:genetics; D015497:HIV-1 / Q000235:genetics* / Q000472:pathogenicity; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000235:genetics*; D007371:Interferon-gamma / Q000276:immunology; D015847:Interleukin-4 / Q000235:genetics; D007630:Kenya / Q000453:epidemiology; D018895:Microsatellite Repeats / Q000235:genetics; D011110:Polymorphism, Genetic / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011477:Sex Work
D050856:Interferon Regulatory Factor-1; D015847:Interleukin-4; D007371:Interferon-gamma