Nuclear pore passage of the HIV capsid is driven by its unusual surface amino acid composition.

Nuclear transport receptors (NTRs) carry cargo across the permeability barrier of nuclear pore complexes (NPCs)-an FG phase condensed from disordered but cohesive FG-repeat domains. This phase repels inert macromolecules but allows NTR passage. When the human immunodeficiency virus (HIV) infects nondividing cells, its capsid is transported into nuclei not like a cargo but crosses NPCs like an NTR. Here we uncovered the molecular determinants of the capsid's NTR behavior. The FG-binding pocket is insufficient. Hexameric and pentameric capsomers contribute. The highly exposed outer capsid surface is key. It lacks FG-repulsive charged residues (K, D and E) that are very abundant on other protein surfaces. FG-attractive residues dominate the capsid surface instead. Introducing FG-repulsive amino acids impedes FG phase partitioning, NPC targeting and NPC passage of assembled capsids. Capsids are, thus, made soluble in the FG phase by a myriad of transient FG-attractive interactions originating from individual surface side chains. We propose that CPSF6 releases the capsid from NPCs by masking its FG-attractive surface and switching the capsid to an FG-repulsive species.