The role of POM121 in HIV-1 infection

Division Of Basic Sciences - Nci

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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 (NPCs) 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. We uncovered an important role of the NPC factor POM121 (an FG-nucleoporin) in HIV-1 nuclear entry. HIV-1 CA binds to POM121 directly. We sought to map this interface. We have identified residues in CA that participate in the interaction. And we have delineated a portion of POM121 that is sufficient to engage CA. We hypothesize the interaction of full length proteins is quite strong based on genetic data. We would like to fully characterize this interaction interface. It is overlapping and distinct to CPSF6 engagement of CA. Given the ability of CPSF6 binders, POM121 binders (when fused to TRIM5alpha), and the antiviral drug Lenacapavir to strongly inhibit HIV-1 infection through targeting this region of CA, it is figuratively an Achilles' heel in early HIV-1 infection. Better defining this area of vulnerability will enable the development of additional therapies to control HIV-1 infection and spread.