D-105 Structural Basis of HIV-1 Capsid Assembly, Maturation And Host Cell Interactions

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HIV-1 capsid plays critical roles in HIV-1 replication by protecting the genome from innate immune sensing response and interacting with many host factors including CypA, CPSF6, M × B, TRIM5α and TRIM-Cyp. We have previously determined the CA tubular assembly to 8 Å using cryoEM and built an all-atom computer model of the complete capsid by large scale molecular dynamics (MD) simulations. Exploiting the recent advance in direct electron detection, we have now obtained the structure of HIV-1 capsid at near-atomic resolution, revealing functionally important elements in an assembly context. Our novel in vitro HIV-1 maturation process and computer simulations further suggest a probable assembly pathway for HIV-1 maturation, which consists a sequential combination of both displacive and disassembly/reassembly processes. We have further determined the structure of the host cell factor CypA in complex with HIV-1 capsid assembly by cryoEM. The density map unexpectedly displays a distinct non-random CypA binding pattern in which CypA bridges 2 adjacent CA hexamers along the curved CA array and stabilizes the viral capsid. CryoEM structure-based modeling and large scale all-atoms MD simulations surprisingly reveal that this unique CypA pattern was achieved through an additional uncharacterized novel interface so that a single CypA molecule simultaneously interacts with 2 CA molecules, therefore, stabilizes and protects the capsid from premature uncoating. Our structure further highlights this novel CypA and CA interface as a potentially attractive therapeutic target for pharmacological intervention.

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