Research Projects

The viral accessory protein Vpx, encoded by HIV-2 and a limited range of SIVs, is essential for the infection of non-dividing myeloid cells. It plays a crucial role in downregulating SAMHD1, a human protein that was first identified almost two decades ago. SAMHD1 is a potent restriction factor for HIV-1, preventing effective reverse transcription of the retroviral genome. Vpx is believed to target SAMHD1 for proteasomal degradation, which is why it was identified as Vpx's raison d'être. Vpx recruits SAMHD1 to the Cullin4-Ring Finger E3 ubiquitin ligase (CRL4) by facilitating an interaction between SAMHD1 and the substrate receptor DDB1- and Cullin4-associated factor 1 (DCAF1). The molecular mechanisms by which these viral proteins interact and manipulate the host ubiquitin-proteosome system are yet to be unraveled. The main goal of this project is to elucidate the interactions of Vpx with the host ubiquitin-proteosome system. The project aims to investigate the details of the mechanism of Vpx/Vpr-CRL4 (DCAF1) E3 ligase assembly through molecular dynamics simulations. The first objective is to investigate how the integrated Vpx-DCAF1 complex binds to different parts of the mammalian protein SAMHD1 based on existing X-Ray structures. The second part involves studying human SAMHD1 bound to Vpx-DCAF1. The third part focuses on searching for small molecules that can disrupt the Vpx-DCAF1-SAMHD1 complexes using in-silico techniques. This research has implications for understanding a complex molecular machine and finding new therapeutic agents targeting Vpx.