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.
(Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)