Cellular IP₆ Levels Limit HIV Production while Viruses that Cannot Efficiently Package IP₆ Are Attenuated for Infection and Replication

TY - JOUR

T1 - Cellular IP6 Levels Limit HIV Production while Viruses that Cannot Efficiently Package IP6 Are Attenuated for Infection and Replication

AU - Mallery, Donna L.

AU - Faysal, K. M.Rifat

AU - Kleinpeter, Alex

AU - Wilson, Miranda S.C.

AU - Vaysburd, Marina

AU - Fletcher, Adam J.

AU - Novikova, Mariia

AU - Böcking, Till

AU - Freed, Eric O.

AU - Saiardi, Adolfo

AU - James, Leo C.

N1 - Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved. 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).

PY - 2019/12/17

Y1 - 2019/12/17

N2 - 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.

AB - 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.

KW - AIDS

KW - capsid

KW - HIV

KW - inositol hexakisphosphate

KW - IP6

KW - IPMK

KW - IPPK

KW - virus

UR - https://www.scopus.com/pages/publications/85076370267

U2 - 10.1016/j.celrep.2019.11.050

DO - 10.1016/j.celrep.2019.11.050

M3 - Article

C2 - 31851928

AN - SCOPUS:85076370267

SN - 2211-1247

VL - 29

SP - 3983-3996.e4

JO - Cell Reports

JF - Cell Reports

IS - 12

ER -