Cellular IP6 levels limit HIV production while viruses that cannot efficiently package IP6 are attenuated for infection and replication

Mallery, D. L. et al. (2019) Cellular IP6 levels limit HIV production while viruses that cannot efficiently package IP6 are attenuated for infection and replication. Cell Reports, 29(12), 3983-3996.e4. (doi: 10.1016/j.celrep.2019.11.050) (PMID:31851928) (PMCID:PMC6931105)

Abstract

Summary: 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.

• Item Type: Articles
• Additional Information: This work was supported by the MRC (UK; U105181010 ), a Wellcome Trust Investigator Award (200594/Z/16/Z), a Wellcome Trust Collaborator Award (214344/A/18/Z), and the NHMRC (Australia; APP1100771 and APP1158338 ). A.S. was supported by the MRC ( MC_UU_00012/4 ).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Fletcher, Dr Adam
• Authors: Mallery, D. L., Faysal, K.M. R., Kleinpeter, A., Wilson, M. S.C., Vaysburd, M., Fletcher, A. J., Novikova, M., Böcking, T., Freed, E. O., Saiardi, A., and James, L. C.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity; College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research
• Journal Name: Cell Reports
• ISSN: 2211-1247
• Copyright Holders: Copyright © 2019 The Author(s)
• First Published: First published in Cell Reports 29(12):3983-3996.e4
• Publisher Policy: Reproduced under a Creative Commons licence