How HIV-1 virions find and selectively package their RNA genome (gRNA) in the presence of over 1000-fold excess of cytoplasmic mRNA that can also support the assembly remains unknown. The only viral protein required for the assembly of the virus like particles (VLPs) is Gag. Gag is only weakly specific for binding to the packaging signal (Psi) of gRNA, insufficient for its selective packaging. As all retroviruses, HIV-1 has an extremely slow rate of gRNA and Gag synthesis that are both products of the single pro-viral gene in the chromatin of the infected cell. We show that the slow rate of VLP assembly on the plasma membrane (PM) of the cell is proportional to the slow rate of Gag synthesis in the steady state (SS) regime of VLP production. Under these conditions RNA molecules that support the fastest VLP assembly will get packaged into the VLPs. Feature of the gRNA molecule that distinguishes it from other long mRNAs besides its weak Psi signal is its strong dimerization propensity via the primary dimerization signal (DIS) within its Psi region. We propose that it is the gRNA dimerization on PM that drives merging of the associated Gag clusters and leads to the selective gRNA dimer packaging. We predict this gRNA packaging selectivity to grow in cells with lower levels of HIV-1 expression—an important notion explaining infectivity of the virions produced in weakly HIV-1 expressing cells. We also predict selective gRNA packaging dependence on the strength of Gag/PM and Gag-Gag interactions and other cellular parameters. Testing of these predictions is in progress, and ideas for novel antiviral strategies and the methods of gene delivery are being considered.
Rouzina et al. (Sun,) studied this question.