Interaction Between HIV-1 Integrase and Viral RNA Drives Proper Virion Morphogenesis and is Necessary for Successful Infection

Abstract Recent findings indicate a key role for the HIV-1 integrase (IN) enzyme in proper virion morphogenesis which involves its binding to viral RNA. Mutations within the IN C-terminal domain potently block IN-RNA interactions leading to the generation of non-infectious particles with “eccentric” morphology with the viral genomic RNA mislocalized outside the capsid core. Despite containing all the components necessary for replication, such particles cannot successfully infect target cells. Interestingly, mutations within IN at residues outside the RNA-binding site cause similar defects. To determine how multiple mutations within IN can lead to similar defects in virion morphology and viral replication, we characterized a panel of IN mutant viruses for defects in the viral lifecycle. Human monocyte-derived macrophages or cultured cells were infected with IN mutant viruses and viral RNA, DNA, and proteins were analyzed by either immunoblot, qPCR, or confocal microscopy. All of the mutant viruses screened were severely attenuated in infectivity, and encountered a block early after entering target cells. Viral RNA and IN were lost from target cells, and reverse-transcribed viral DNA did not accumulate. These findings support a model in which the viral capsid core is critical for protecting entering viral RNA and replicative enzymes from the host environment.