The functional role of IRF1 polymorphisms in susceptibility to HIV-1 infection

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Sivro, Aida
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Altered susceptibility to HIV-1 infection has been observed in multiple cohort studies around the world, with a small proportion of HIV-Exposed, Seronegative (HESN) individuals remaining uninfected despite repeated exposure. Previous work has shown association of three polymorphisms in interferon regulatory factor 1 (IRF1) with decreased susceptibility to HIV-1 infection and a reduced likelihood of seroconversion. Peripheral blood mononuclear cells (PBMCs) from patients with protective IRF1 haplotype exhibited significantly lower basal IRF1 expression, reduced responsiveness to IFNγ stimulation and significantly lower HIV-1 LTR transcription during the initial stages of infection. The goal of this thesis was to characterize the effect of three IRF1 polymorphisms associated with HIV-resistant phenotype on: (1) IRF1 gene transcription, alternative splicing of IRF1 mRNA and IRF1 mRNA/protein stability (2) plasma and cervical lavage (CVL) cytokine/chemokine expression and (3) HIV pathogenesis and disease progression. Furthermore since differences in hormone expression are known to regulate IRF1 function we set out to determine if differences in plasma hormone levels contribute to the natural resistance against HIV-1 infection in the Majengo HESN cohort. Polymorphisms in the IRF1 gene do not directly affect IRF1 transcription but instead act as intronic splicing regulators. PBMCs from individuals with protective IRF1 haplotype were associated with increased inclusion of exons 7/8 and decreased protein stability when compared to cells from individuals with nonprotective haplotype. Individuals with protective IRF1 haplotype also exhibited significantly higher plasma IL15, IFNγ and IL6 expression and significantly higher CVL IL15, IFNγ, IL2 and sIL2Rα expression (with univariate analysis only) compared to those with nonprotective IRF1 haplotype. Additionally, individuals with protective IRF1 haplotype expressed significantly lower levels of plasma prolactin when compared to individuals with nonprotective haplotype. IRF1 polymorphisms were found to not be associated with HIV disease progression, suggesting that the protective effect of IRF1 polymorphisms is limited to the early stages, prior to establishment of HIV-1 infection. Furthermore, independent of IRF1 genotypes, significantly lower plasma prolactin, estrogen, progesterone and cortisol levels were observed in HESN women suggesting that hormonal regulation may be one of the main factors regulating natural resistance to HIV-1 infection in the Majengo HESN cohort.