Energetic and kinetic criteria for assembling HIV-1 Gag lattices in solution

For cells infected by the HIV-1 virus, forming new virions requires self-assembly of the

retroviral Gag polyprotein into a spherical lattice. However, quantifying the kinetic and energetic

requirements to promote lattice formation is challenging due to the higher-order contacts needed

for assembly. Here, we use a reaction-diffusion model designed from the cryo-EM structure of

the immature Gag lattice to map out a phase diagram of assembly outcomes. We find a narrow

regime of parameters that can support efficient assembly without the time-dependent release of

monomers due to the large size of this ~3700 monomer complex. Nucleation of multiple Gag

lattices is difficult to suppress before any individual structure completes, even over ~100

seconds, resulting in loss of free monomers and frequent kinetic trapping. We derive rates to

titrate or activate Gag proteins into their solution volume and show how we can recover a high

yield of completed structures, thus avoiding kinetic traps. This strategy can mimic mechanisms

used by cells, where co-factors and membrane binding can provide similar time-dependent

mechanisms of cooperative control. Our work provides a foundation for predicting how these

essential factors regulate Gag lattice formation.