Abstract
The host cell factor cyclophilin A (CypA) interacts directly with the HIV-1 capsid and regulates viral infectivity. Although the crystal structure of CypA in complex with the N-terminal domain of the HIV-1 capsid protein (CA) has been known for nearly two decades, how CypA interacts with the viral capsid and modulates HIV-1 infectivity remains unclear. We determined the cryoEM structure of CypA in complex with the assembled HIV-1 capsid at 8-Å resolution. The structure exhibits a distinct CypA-binding pattern in which CypA selectively bridges the two CA hexamers along the direction of highest curvature. EM-guided all-atom molecular dynamics simulations and solid-state NMR further reveal that the CypA-binding pattern is achieved by single-CypA molecules simultaneously interacting with two CA subunits, in different hexamers, through a previously uncharacterized non-canonical interface. These results provide new insights into how CypA stabilizes the HIV-1 capsid and is recruited to facilitate HIV-1 infection.
Highlights
The host cell factor cyclophilin A (CypA) interacts directly with the HIV-1 capsid and regulates viral infectivity
Binding of CypA to the CypA-binding loop of the viral capsid is essential for viral infectivity[25,26], as substitutions in loop residues G89 or P90 in HIV-1 capsid protein (CA) are deleterious to replication[14,21,27]
We began our studies by characterizing the binding of CypA to HIV-1 CA tubular assemblies at various CypA:CA molar ratios
Summary
The host cell factor cyclophilin A (CypA) interacts directly with the HIV-1 capsid and regulates viral infectivity. EM-guided all-atom molecular dynamics simulations and solid-state NMR further reveal that the CypA-binding pattern is achieved by single-CypA molecules simultaneously interacting with two CA subunits, in different hexamers, through a previously uncharacterized non-canonical interface. These results provide new insights into how CypA stabilizes the HIV-1 capsid and is recruited to facilitate HIV-1 infection. While CypA promotes HIV1 reverse transcription in human cells, its cell-type specific effect is best correlated with nuclear entry, and probably involves an unknown CypA-dependent host restriction factor[24] Owing to this complexity, understanding the role of CypA in HIV-1 infection has been difficult, especially given the limited structural information that is available.
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