(193v) Coarse-Grained Molecular Simulations Reveal Regulatory Insights into Immature HIV-1 Assembly Dynamics

The packaging and release of immature human immunodeficiency virus-1 (HIV-1) particles from host cells is a critical step in the viral replication cycle. Disrupting this highly-regulated process is a potential target for anti-retroviral treatments. It is well-known that Gag (group-specific antigen) polyprotein must multimerize into an immature lattice, which is also bound to a dimer of the viral ribonucleic acid (RNA) and is enveloped by the cell membrane. However, the molecular details of Gag assembly, especially as influenced by the presence of RNA and the cell membrane, remain unclear. To explore these dynamics, we developed a coarse-grained (CG) computational model that is derived from sub-nanometer resolution structural data and investigated the mechanisms that work in concert between Gag polyproteins, RNA, and the membrane to promote immature lattice growth. Our analysis, which is further supported by single particle tracking photoactivated localization experiments, demonstrates that viral RNA and the membrane are critical constituents that expedite Gag multimerization through scaffolding while short competitor RNA suppresses assembly. We also discuss the importance of weak anisotropic interactions at the helical spacer peptide 1 junction to mitigate defects in the otherwise continuous and hexameric Gag lattice. Finally, we reveal that lattice growth kinetics appears to be coupled to membrane deformation dynamics owing to intrinsic curvature that develops in the protein lattice. Overall, these findings elucidate a simple network of interactions that regulate the early stages of HIV-1 assembly and budding.