Inhibition of lentiviral nuclear import pathways by Mx2

PROJECT SUMMARY/ABSTRACT Lentiviruses such as HIV-1 are uniquely efficient in their ability to infect non-dividing cells through the hijacking of cellular nucleocytoplasmic trafficking pathways. Nuclear import of primate lentiviruses is inhibited by the interferon inducible GTPase Mx2, which localizes to the nuclear pore complex. However, the process by which HIV-1 utilizes cellular nucleocytoplasmic trafficking and how nuclear entry is inhibited by Mx2 remain poorly defined. Furthermore, the relationship between Mx2 and other cellular proteins that affect the pre-integration stages of HIV-1 infection is not understood. We have previously demonstrated that the antiviral activity of Mx2 is affected by cellular nucleocytoplasmic trafficking pathways in a cell-type, cell-cycle, and HIV-1 capsid- dependent manner. We further determined that Mx2 inhibits nucleocytoplasmic trafficking of non-viral cargo in a cell-type dependent manner, indicating that it may have broader functions in antiviral interferon responses. Here, we aim to determine how Mx2 is localized to the nuclear pore complex, the nuclear import pathways that are inhibited by Mx2, how Mx2 is affected be heterogeneity in nucleocytoplasmic trafficking, and how Mx2 affects the interaction of HIV-1 with other antiviral proteins.