DNA unwinding by Viral Protein R Initializes Complicated Cellular Responses in HIV-1 Infection: Defining the Viper’s First Bite

Vpr, an accessory gene of human immunodeficiency virus (HIV) type1 that encodes a virion-associated protein, induces multiple cellular responses, e.g. transcriptional regulation, chromatin modulation and the DNA damage response with cell-cycle checkpoint activation. Vpr may promote HIV-1 infection of quiescent cells, including resting macrophages, but it remained elusive how Vpr contributes to viral infection into these cells. With the object of clarifying the role of Vpr, we first summarize the pleiotropic function of Vpr in the HIV-1 life cycle and subsequently the recently identified mode of Vpr-induced DNA damage triggered by unwinding of DNA in association with viral DNA integration. Finally, we discuss the role of Vpr in HIV-associated diseases, which are important issues for HIV-1–infected patients in the post-antiretroviral therapy era.