The host protein cyclophilin A restricts nuclear entry of HIV-1 mutants by reducing the elasticity of the viral capsid

Binding of the host protein cyclophilin A (CypA) to the viral capsid exerts multiple effects on HIV-1 infection, including enhancement of reverse transcription, stabilization of the capsid, and promotion of nuclear entry. CypA can also inhibit infection of selected HIV-1 mutants by a poorly understood mechanism. Using atomic force microscopy methods, we previously showed that HIV-1 cores are highly elastic and that mutants with reduced capsid elasticity are impaired for nuclear entry and infection of nondividing cells. Here we demonstrate that binding of CypA to the capsids of such mutants inhibits their nuclear entry by further reducing the elasticity of their capsids. These effects were reversed by suppressor mutations that restored elasticity to the mutant capsids. Our results define the mechanism by which CypA controls HIV-1 nuclear entry. We hypothesize that nuclear entry involves temporal modulation of capsid elasticity by host proteins prior to and during passage through the nuclear pore.