HIV-1 Capsid Elasticity and Nuclear Entry: A Novel Perspective on Infection

HIV-1 infection requires passage of the reverse transcribing viral
core through the nuclear pore of the cell, a process that depends on
properties of the viral capsid. Recent studies have suggested that
HIV-1 cores can pass through the nuclear pore without prior
disassembly of the viral capsid. Interactions with the nuclear pore
complex are apparently necessary but not sufficient for nuclear
entry, as substitutions in regions of the CA protein that are distinct
from known protein binding sites can result in impaired nuclear
entry. Here we show that the HIV 1 core is highly elastic and that
this feature is linked to nuclear entry and infectivity. Using a novel
atomic force microscopy-based approach, we found that purified
wild type cores return to their normal conical morphology
following a severe forced compression. By contrast, cores from two
nuclear entry-defective CA mutants underwent breakage upon
compression. A suppressor mutation restored elasticity and
infectivity to one of these mutants. Core elasticity was reduced by
addition of concentrations of the capsid-binding antiviral drugs
Lenacapavir and PF74 that inhibit nuclear entry. Our results
indicate that capsid elasticity is a fundamental property of the HIV1 core that enables its passage through the nuclear pore complex,
thereby facilitating infection. These results provide new insights
into the mechanisms of HIV-1 nuclear entry and the antiviral
mechanisms of HIV-1 capsid inhibitors.