HIV-2 Vpx Protein Interacts with Interferon Regulatory Factor 5 ( IRF5) and Inhibits Its Function

Background: HIV-2 Vpx modulates innate immunity by overcoming restrictions for infection of myeloid cells. Results: Vpx binds IRF5 and inhibits its ability to bind to IL6, IL12, and TNF promoters. Conclusion: Effects of Vpx on the innate immune system are at least partially due to its inhibition of TLR activation of IRF5. Significance: Understanding the mechanism of HIV immunomodulation is critical for vaccine development. Interferon regulatory factor (IRF) family members have been implicated as critical transcription factors that function in immune responses, hematopoietic differentiation, and cell growth regulation. Activation of IRF5 results in the production of pro-inflammatory cytokines such as TNF, IL6, and IL12, as well as type I interferons. In this study, we demonstrate that HIV-2 Vpx interacts with IRF5, and Vpx inhibits IRF5-mediated transactivation. Expression of Vpx in THP-1 cells reduced mRNA levels and protein production of Toll-like receptor-dependent IL6, IL12p40, and TNF induced by lipopolysaccharide, R848, and ODN2216. Chromatin immunoprecipitation assays show that Vpx expression results in decreased promoter binding activity of IRF5. This study provides new insights into mechanisms employed by HIV-2 to counteract innate immune defenses against viral infection.