The host protein cyclophilin A inhibits HIV-1 nuclear entry by decreasing capsid elasticity

Hong, J.; Deshpande, A.; Thakare, Y.; Simonovsky, L.; Douglas, A. W.; Mc Guinness, C.; Rotem-Dai, N.; Kortyna, M. L.; Klarhof, J. O.; Shi, J.; Boecking, T.; James, L. C.; Francis, A. C.; Rousso, I.; Aiken, C.

doi:10.1101/2025.09.03.673798

bioRxiv · 10.1101/2025.09.03.673798

The host protein cyclophilin A inhibits HIV-1 nuclear entry by decreasing capsid elasticity

Hong, J.·Deshpande, A.·Thakare, Y.·Simonovsky, L.·Douglas, A. W.·Mc Guinness, C.·Rotem-Dai, N.·Kortyna, M. L.·Klarhof, J. O.·Shi, J.·Boecking, T.·James, L. C.·Francis, A. C.·Rousso, I.·Aiken, C.

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Abstract

Binding of the host protein cyclophilin A (CypA) to the HIV-1 capsid exerts a variety of effects on infection, including enhancement of reverse transcription, stabilization of the capsid, and promotion of nuclear entry. For several HIV-1 mutants, CypA binding inhibits nuclear entry by an unknown mechanism. We recently demonstrated that HIV-1 cores are elastic and that HIV-1 mutants with inelastic capsids are impaired for nuclear entry and infection of nondividing cells. Here we show that CypA prevents infection of nondividing cells by such mutants and inhibits their entry into the nucleus. CypA binding to mutant cores further reduced their elasticity in vitro, and this effect was reversed by suppressor mutations that restored nuclear entry. We suggest that HIV-1 nuclear entry involves temporal modulation of capsid elasticity by host proteins prior to and during traversal of the nuclear pore.

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Hong, J., Deshpande, A., Thakare, Y., Simonovsky, L., Douglas, A. W., Mc Guinness, C., Rotem-Dai, N., Kortyna, M. L., Klarhof, J. O., Shi, J., Boecking, T., James, L. C., Francis, A. C., Rousso, I., Aiken, C.. 2025-09-03. The host protein cyclophilin A inhibits HIV-1 nuclear entry by decreasing capsid elasticity. https://doi.org/10.1101/2025.09.03.673798

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