HIV-1 Ribonucleoprotein Complex Organization Facilitates Assembly of the Mature HIV-1 Capsid

The encapsulation of the viral RNA condensate inside the capsid is a crucial step in the late stages of the HIV-1 replication cycle. While it is agreed that RNA encapsulation depends on RNA-bound integrase (IN), that capsid-bound IN-RNA filaments are present within the capsid, and that the ribonucleoprotein (RNP) complex takes up only a fraction of the capsid volume, the timing of filament formation and ribonucleoprotein (RNP) encapsulation are unclear. Here, we ran virion-scale, coarse grained molecular dynamics simulations to identify how the organization of the RNP and IN in particular affects mature capsid assembly and genome encapsulation. These virion-scale simulations allow for direct comparison between experimental capsid morphologies and those self-assembled in the simulations. It was found, when relatively few tetramers are on the RNP surface, that IN tetramers could facilitate RNA encapsulation without filling a significant fraction of the capsid volume, but do not form a capsid-templated filament. When octameric IN-RNA filaments are modeled, it was found that WT-like capsid morphologies form only when the IN is organized as a single long filament, in agreement with recent experimental suggestions. These capsids are more conical and elongated than the capsids assembled around the RNP with tetrameric IN. Thus, we suggest the IN-RNA filament assembles ahead of the capsid and directs it to its final conical morphology, consistent with the experimental observation of less elongated capsids when IN oligomerization is disrupted.