Crucially, LEN and PF74 rapidly expose previously hidden HIV-1 genomes. These genomes are integration-competent: short LEN pulses actually increase the amount of integrated provirus in macrophages, showing that exposed genomes are functionally complete and can finish infection.

This finding in context of other data directly suggests a possible mechanism: flattening of the lattice predominantly in pentamer-dense regions leads to rupture of capsids.

Using CLEM-ET, we uncover a distinct structural damage signature: LEN induces "lobster-like" bifurcated protrusions at the narrow end of the conical capsid and leaves behind apparently fused lattice remnants.

We find that intact and broken capsids cluster in nuclear speckles of primary macrophages. When we add LEN or PF74, capsid-associated CPSF6 is displaced, and these subviral complexes rapidly exit nuclear speckles. So capsid inhibitors actively re-route nuclear HIV complexes.