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

AIDS. 2007 May 31;21(9):1091-101. doi: 10.1097/QAD.0b013e3280ef6ae1.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Cross-Sectional Studies
  • Female
  • Gene Expression Regulation, Viral / genetics
  • Genes, Viral / genetics*
  • Genetic Predisposition to Disease / genetics
  • Genotype
  • HIV Infections / epidemiology
  • HIV Infections / genetics*
  • HIV Infections / transmission
  • HIV Seropositivity / genetics
  • HIV-1 / genetics*
  • HIV-1 / pathogenicity
  • Haplotypes / genetics
  • Humans
  • Interferon Regulatory Factor-1 / genetics*
  • Interferon-gamma / immunology
  • Interleukin-4 / genetics
  • Kenya / epidemiology
  • Microsatellite Repeats / genetics
  • Polymorphism, Genetic / genetics*
  • Polymorphism, Single Nucleotide / genetics
  • Sex Work

Substances

  • Interferon Regulatory Factor-1
  • Interleukin-4
  • Interferon-gamma