Year: 2026
Type: preprint
Abstract: A crucial stage of the HIV-1 life cycle is the docking of the viral capsid at, and its translocation through, the nuclear pore complex (NPC). During this process, the capsid interacts with a series of cellular host factors that regulate efficient nuclear entry. One such host factor is cleavage and polyadenylation specificity factor 6 (CPSF6), which plays a critical role in efficient HIV-1 nuclear entry and integration. Experimental evidence suggests that nucleoporins (NUPs), such as NUP153, initially engage the capsid, followed by CPSF6 binding and oligomerization during subsequent stages of nuclear import. However, the mechanistic basis by which CPSF6 binds to the capsid and subsequently oligomerizes remains poorly understood. To address this question, we have developed bottom-up coarse-grained (CG) models that explicitly simulate the process of CPSF6 binding and oligomerization on the HIV-1 capsid. Our simulations show that CPSF6 assembles into a mesh-like coating surrounding the capsid, consistent with experimental observations. Furthermore, we then demonstrate that CPSF6 binding is dependent on the intrinsic curvature of the capsid lattice. Finally, we investigate how perturbing CPSF6-CPSF6 interactions alters binding, oligomerization dynamics, and curvature dependence. Together, these findings provide new mechanistic insights into how CPSF6 regulates HIV-1 nuclear entry.
Authors: Arpa Hudait, Kuntal Ghosh, Gregory A. Voth
Institution: University of Chicago
Language: English
Topic: HIV Research and Treatment
Subfield: Virology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
Awards: G1453181110, Track 4: Advanced CI Coordination Ecosystem: Monitoring and Measurement Services, Computation for the Endless Frontier, G3037948166, G3503245242, G3562386289, Track 1: ACCESS Resource Allocations Marketplace and Platform Services (RAMPS), G4010157413, ACO: An Open CI Ecosystem to Advance Scientific Discovery (OpenCI), G4774908964, G478808451, G4965851914, Track 3: COre National Ecosystem for CyberinfrasTructure (CONECT), G5367127336, G5464919783, G6309863580, G6316823789, G8297442250, Track 2: Customized Multi-tier Assistance, Training, and Computational Help (MATCH) for End User ACCESS to CI, G890701178, Behavior of HIV in Viral Environments (B-HIVE)
OpenAlex ID: W7212087547