Cryo-ET Reveals Distinct Gag Lattice Architectures in Virus-like Particles and Immature HIV-1

HIV-1 is released from infected cells as immature virions whose membranes are supported by a Gag lattice. During maturation, this lattice is cleaved by the viral protease to release capsid proteins that assemble into the mature core. The architecture of the Gag lattice is central to this process, and the Gag lattice is targeted by maturation inhibitors that block cleavage. Using cryo-electron tomography, we compared Gag-only virus-like particles (VLPs) with immature HIV-1 virions and found that VLPs assemble denser and more complete lattices, exhibiting a strong correlation between lattice curvature and Gag copy number. In contrast, immature virions incorporate fewer Gag molecules and display weaker coupling between curvature and Gag stoichiometry. These findings show that while Gag alone can form the canonical immature lattice, additional viral components fine-tune lattice organization and curvature, potentially regulating protease accessibility, virion release, and the onset of HIV-1 maturation.