HIV accessory Protein Vpr Attenuates the Host Innate Immune Response Through Ablation of NF-kB Signaling

Human Immunodeficiency Virus (HIV) has caused a devastating global epidemic for over 30 years.  Despite dedicated efforts, vaccines or therapies to clear HIV infection have not yet been discovered.  Viral accessory protein vpr has been found to suppress the cellular immune response, but its mechanism of action remains unknown.  Vpr degrades an unidentified host cell protein by recruiting it to the DCAF-1/DDB1/Culllin 4 ubiquitin ligase complex, where the protein is polyubiquitinated and targeted for proteasomal degradation.  We hypothesized that vpr attenuates an essential innate inflammatory pathway through degradation of a critical signaling molecule.  Activity of numerous transcription factors involved in immune signaling was tested for deregulation by vpr using a luciferase reporter system.  Upstream components of pathways found to be modulated by vpr were subjected to co-immunoprecipitation and western blot analysis to determine a direct interaction with vpr.  Nuclear factor kappa B (NF-kB) dependent transcription was found to be ablated by over-expression of vpr.  NF-kB signaling is essential for mounting an immune response.  Attenuation of NF-kB signaling by vpr is an important mechanism of vpr-mediated immune suppression.  Elucidation of the precise mechanism of vpr-mediated NF-kB suppression will facilitate the design of future therapeutics for HIV-infected patients.