In order for HIV-1 to integrate its genome into its host chromosome, the HIV-1 core must first coordinate docking, uncoating, and pre-integration complex (PIC) entry into the nucleus through the nuclear pore complex (NPC). Whereas the HIV-1 reverse transcription and integration steps are relatively well understood, the process of HIV-1 import through the nuclear pore remains poorly characterized
The Torbett lab is working towards addressing the unmet need for mechanistic and structural information on HIV-1 nuclear import, a complex process that could be targeted for novel antiviral therapy. We hypothesize that HIV-1 transport through the NPC involves multiple sequential interactions of viral components (including the capsid core) with different NUPs and novel host factors; such interactions are associated with dynamic changes in the virus and NPC structures. Specifically, we are working towards developing novel approaches to elucidate the molecular mechanisms involved in HIV-1 transport through the NPC by engineering strategies to block the inner ring of the NPC in order to study HIV-1 docking and initial entry into the NPC.
We are also engineering strategies to study the second half of transport through the NPC (HIV-1 exiting the inner ring and transport through the nuclear basket) by clogging the basket of NPC and identifying viral and host factor proteins that interact with the NPC basket during HIV-1 nuclear import.