title: Reduced HIV-1 long terminal repeat transcription in subjects with protective interferon regulatory factor-1 genotype: a potential mechanism mediating resistance to infection by HIV-1.
abstract: We previously described the polymorphism in the interferon regulatory factor-1 (IRF-1) gene as a novel correlate of resistance to HIV-1 infection in a Kenyan female sex worker cohort. However, the underlying mechanisms likely mediating this association remained to be elucidated. The initiation of HIV-1 long terminal repeat (LTR) transcription in peripheral blood mononuclear cells (PBMCs) from subjects with different IRF-1 haplotypes, representing protective, intermediate and the least protective IRF-1 allele combinations, were investigated here. A single-cycle pseudovirus construct expressing vesicular stomatitis virus envelop G-protein (VSV-G) and having an HIV-1 pNL4.3 backbone with luciferase insert was used to infect PBMCs with different IRF-1 haplotypes. The efficiency of early HIV-1 LTR transcription was monitored using a luciferase assay. IRF-1 protein levels induced by the infection were measured by quantitative Western blot. Our results showed that PBMCs with the protective IRF-1 genotype demonstrated significantly lower HIV-1 LTR transcription during the initial stages of infection compared to PBMCs with other haplotypes, which correlated with the kinetics of IRF-1 responsiveness to HIV-1 infection in the cells. It suggests that IRF-1 genotypes alter the efficiency of early HIV-1 LTR transcription, likely via modulating expression of IRF-1. This may represent one mechanism mediating the association between IRF-1 polymorphisms and resistance to HIV-1 infection.
authors.affiliation: Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, Manitoba, Canada. hezhao_ji@phac-aspc.gc.ca
authors.forename: Hezhao
authors.initials: H
authors.lastname: Ji
authors.forename: Terry Blake
authors.initials: TB
authors.lastname: Ball
authors.forename: Zhujun
authors.initials: Z
authors.lastname: Ao
authors.forename: Joshua
authors.initials: J
authors.lastname: Kimani
authors.forename: Xiaojian
authors.initials: X
authors.lastname: Yao
authors.forename: Francis Allan
authors.initials: FA
authors.lastname: Plummer
mesh_terms: D015153:Blotting, Western; D002478:Cells, Cultured; D005260:Female; D017930:Genes, Reporter; D005838:Genotype; D016325:HIV Long Terminal Repeat / Q000235:genetics*; D015497:HIV-1 / Q000254:growth & development*; D006801:Humans; D007113:Immunity, Innate; D050856:Interferon Regulatory Factor-1 / Q000096:biosynthesis / Q000235:genetics*; D007630:Kenya; D007963:Leukocytes, Mononuclear / Q000821:virology; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D011110:Polymorphism, Genetic; D014158:Transcription, Genetic; D018116:Vesiculovirus / Q000235:genetics
chemical_list: D050856:Interferon Regulatory Factor-1; D008156:Luciferases