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.

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Mechanosensitive nuclear pores The nucleus of eukaryotic cells is enclosed by the nuclear envelope, a double membrane punctuated with nuclear pore complexes (NPCs). These giant channels in the nuclear envelope mediate nucleocytoplasmic exchange. Zimmerli et al . show that the mechanical status of the nuclear membranes controls their nuclear pore diameter. Pulling forces imposed through nuclear membranes lead to stretching of NPCs and dilation of their diameter, whereas relief of such forces causes NPC constriction. Thus, the control of nuclear size and shape is functionally linked with NPC conformation and nucleocytoplasmic transport activity. —SMH