HIV-1 passage through the nuclear pore complex

Division Of Basic Sciences - Nci

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Abstract

How HIV-1 migrates through the nuclear pore complex (NPC) can influence where it integrates its genome in host cell chromatin. Given the use of HIV-1 derived lentiviral vectors in gene therapy, including the establishment of anticancer CAR T cells (a type of immunotherapy), the elucidation of mechanisms employed by HIV-1 to traffic through the NPC could be beneficial in developing improved vectors for gene therapy. To investigate the role of nuclear pore subcomplexes in HIV-1 infection, we systematically depleted all thirty-two human nuclear pore proteins in HeLa cells with siRNA, and then infected with VSV-G pseudotyped reporter viruses. In this effort, we have identified HIV-1 dependency on nucleoporins that are regulated by CA interactions with CypA. Strikingly, CypA dictates the nuclear import route utilized by HIV-1, favoring an FG-receptor mediated pathway. We hypothesize that CypA regulates access the N74 pocket of HIV-1 CA and facilitates subsequent interaction with FG-nucleoporins. Similar findings have been observed by other groups. CA interaction with CypA is mediated by residues proximal to the N74 pocket. We wish to understand if this region of HIV-1 is sufficient to confer CA interaction with the NPC using other retroviral cores and whether a role of CypA is preserved, or it is unnecessary in a different context.