How SLX4 cuts through the mystery of HIV-1 Vpr-mediated cell cycle arrest

Vpr is one of the most enigmatic viral auxiliary proteins of HIV. During the past twenty years, several activities have been ascribed to this viral protein, but one, its ability to mediate cell cycle arrest at the G2 to M transition has been the most extensively studied. Nonetheless, the genuine role of Vpr and its pathophysiological relevance in the viral life cycle have remained mysterious. Recent work by Laguette et al. (Cell 156:134-145, 2014) provides important insight into the molecular mechanism of Vpr-mediated G2 arrest. This study highlights for the first time how Vpr recruits the SLX4 endonuclease complex and how Vpr-induced inappropriate activation of this complex leads to G2 arrest. Here, we will discuss these findings in the light of previous work to show how they change the view of Vpr’s mechanism of action. We will also discuss how these findings open new questions towards the understanding of the biological function of Vpr regarding innate immune sensing.