Cellular IP₆ Levels Limit HIV Production while Viruses that Cannot Efficiently Package IP₆ Are Attenuated for...

HIV-1 hijacks host proteins to promote infection. Here we show that HIV is also dependent upon the host metabolite inositol hexakisphosphate (IP₆) for viral production and primary cell replication. HIV-1 recruits IP₆ into virions using two lysine rings in its immature hexamers. Mutation of either ring inhibits IP₆ packaging and reduces viral production. Loss of IP₆ also results in virions with highly unstable capsids, leading to a profound loss of reverse transcription and cell infection. Replacement of one ring with a hydrophobic isoleucine core restores viral production, but IP₆ incorporation and infection remain impaired, consistent with an independent role for IP₆ in stable capsid assembly. Genetic knockout of biosynthetic kinases IPMK and IPPK reveals that cellular IP₆ availability limits the production of diverse lentiviruses, but in the absence of IP₆, HIV-1 packages IP₅ without loss of infectivity. Together, these data suggest that IP₆ is a critical cofactor for HIV-1 replication.