Viral Protein X (Vpx) Unlocks Nuclear Pore Complex through human Nup153 Dependent Pathway to Promote Nuclear Translocation of Lentiviral Genome
Simian Immunodeficiency Virus (SIV) and Human Immunodeficiency Virus 2 (HIV-2) display unique ability to infect non-dividing target cells. Viral protein X (Vpx) of HIV-2/SIV is known to be involved in the nuclear import of viral genome in non-dividing cells, but the mechanism remains poorly understood. In the present investigation for the first time, we provided evidence that Vpx of SIVsmPBj1.9 physically interacts with human Nup153, which is known to provide a docking site for protein-cargo complexes at the nuclear pore complex (NPC). Results from Super Resolution-Structured Illumination Microscopy (SR-SIM) studies reveal that Vpx interaction with NPC associated Nup153 is critical for its efficient nuclear translocation. Virion-associated MAPK/ERK-2 mediated phosphorylation of Vpx plays a critical role for its interaction with human Nup153 and this interaction was found to be evolutionarily conserved in various SIV isolates and HIV-2. Interestingly, MAPK/ERK-2 packaging defective SIV failed to promote the efficient nuclear import of viral genome suggest that MAPK/ERK-2 mediated Vpx phosphorylation is important for its interaction with Nup153, which is critical for lentiviruses to establish infection in non-dividing target cells. Together, our data elucidate the mechanism by which Vpx orchestrates the challenging task of nuclear translocation of HIV-2/SIV genome in non-dividing target cells.



