Cellular IP6 Levels Limit HIV Production while Viruses that Cannot Efficiently Package IP6 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 (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. [Display omitted] •HIV needs cellular IP6 to efficiently produce and assemble virions•HIV packages IP6 using two rings of lysine residues in immature gag hexamers•Viruses that fail to package IP6 do not mature properly and have unstable capsids•Deficient IP6 packaging prevents HIV replicating in primary cells Mallery et al. demonstrate that HIV is crucially dependent upon the host metabolite IP6 to produce infectious virions. Cells deficient in IP6 produce fewer virions, while virions that fail to package sufficient numbers of IP6 molecules are poorly infectious and fail to replicate in primary cells.