The role of POM121 in HIV-1 infection

Division Of Basic Sciences - Nci

Investigators

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Abstract

The HIV-1 core, composed as a lattice of CA hexamers and pentamers, engages FG-nucleoporins to enable transport of the virus through nuclear pore complexes to access host cell chromatin. The choreography of this interaction, specifically which nucleoporins are engaged in what order, and the multivalency of this interaction, specifically which interactions are overlapping and which might be displaced, are key issues that need to be resolved to better understand the mechanism of HIV-1 nuclear entry. HIV-1 CA mediates these interactions and is highly vulnerable to antiviral therapy because of the central role that CA plays in engaging possibly a dozen or more host factors through the same interface. How HIV-1 migrates through the nuclear pore complex also affects 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, the elucidation of this biology could be beneficial in developing improved vectors for gene therapy. The interaction of HIV-1 CA with POM121 appears to be one of the strongest ones in the cell based on TRIM5 fusion protein analysis. We thus want to define more precisely the interaction surfaces. Based on the subcellular localization of POM121, we expect this interaction to be early in the nuclear entry process. This is also consistent with regulation by CypA. We will use the domain interaction studies as a basis to help understand how CypA governs use of POM121 and what role POM121 plays in HIV-1 migration through the nuclear pore complex. Finally, there are other isoforms of POM121 - POM121C and soluble POM121. We are examining whether they affect HIV-1 infection and whether conserved domains are contributing to interactions with HIV-1 CA.