Cone-shaped HIV-1 capsids are transported through intact nuclear pores

Highlights

• Nuclear translocation of HIV-1 capsids is captured by 3D CLEM/cryo-ET

• Nuclear pore complexes in T cells are sufficiently dilated to accommodate HIV-1 capsids

• Cone-shaped HIV-1 capsids translocate through nuclear pore complexes

• Inside the nucleus HIV-1 capsids rupture and release their interior

Summary

Human immunodeficiency virus (HIV-1) remains a major health threat. Viral capsid uncoating and nuclear import of the viral genome are critical for productive infection. The size of the HIV-1 capsid is generally believed to exceed the diameter of the nuclear pore complex (NPC), indicating that capsid uncoating has to occur prior to nuclear import. Here, we combined correlative light and electron microscopy with subtomogram averaging to capture the structural status of reverse transcription-competent HIV-1 complexes in infected T cells. We demonstrated that the diameter of the NPC in cellulo is sufficient for the import of apparently intact, cone-shaped capsids. Subsequent to nuclear import, we detected disrupted and empty capsid fragments, indicating that uncoating of the replication complex occurs by breaking the capsid open, and not by disassembly into individual subunits. Our data directly visualize a key step in HIV-1 replication and enhance our mechanistic understanding of the viral life cycle.