Cellular IP(6) Levels Limit HIV Production while Viruses that Cannot Efficiently Package IP(6) Are Attenuated for Infection and Replication

HIV-1 hijacks host proteins to promote infection. Here we show that HIV is also dependent upon the host metabolite inositol hexakisphosphate (IP(6)) for viral production and primary cell replication. HIV-1 recruits IP(6) into virions using two lysine rings in its immature hexamers. Mutation of either ring inhibits IP(6) packaging and reduces viral production. Loss of IP(6) 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 IP(6) incorporation and infection remain impaired, consistent with an independent role for IP(6) in stable capsid assembly. Genetic knockout of biosynthetic kinases IPMK and IPPK reveals that cellular IP(6) availability limits the production of diverse lentiviruses, but in the absence of IP(6), HIV-1 packages IP(5) without loss of infectivity. Together, these data suggest that IP(6) is a critical cofactor for HIV-1 replication.