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Biophysics in the Understanding, Diagnosis, and Treatment of Infectious Diseases Speaker Abstracts
10
Structural Basis of HIV-1 Capsid Assembly and Host Cell Interactions
Peijun Zhang
.
University of Pittsburgh School of Medicine, Pittsburgh, USA.
The mature HIV-1 capsid plays a major role in the early stages of HIV-1 replication by
protecting the genome from innate immune sensing response and regulating infection by
interacting with many host factors including CypA, CPSF6, MxB, TRIM5α and TRIM-Cyp. It
contains two structural domains that are connected by a flexible linker and assembles into a
distinct cone shaped capsid that encloses the viral genome. 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, clearly resolving bulky side chain densities, helix grooves and connecting loops. For
the first time, the flexible linker and the major homology region are clearly visualized in an
assembly context, providing insights on their critical roles in capsid assembly and maturation.
We have also determined the cryoEM structure of the host cell factor CypA in complex with
HIV-1 capsid assembly. The density map unexpectedly displays a distinct non-random CypA
binding pattern in which CypA bridges two adjacent CA hexamers and wraps selectively along
the curved CA array. CryoEM structure-based modeling and large scale all-atoms MD
simulations surprisingly reveal that the unique CypA pattern was achieved through an additional
uncharacterized novel interface so that a single CypA molecule simultaneously interacts with
two 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.