Abstract
SummaryHIV-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.
Highlights
The HIV-1 capsid undergoes a number of transformations during viral replication: assembly, maturation, host interaction, and uncoating
IP6 biosynthesis is a complex metabolic pathway involving the conversion of IP3 to IP5 by inositol polyphosphate multikinase (IPMK or IPK2), followed by phosphorylation of IP5 to IP6 by inositol-pentakisphosphate 2-kinase (IP5-2K, IPPK, or IPK1) (Figure 1A)
As previous work has shown that genetic deletion of IPMK in mouse embryonic stem cells (ESCs) leads to a marked reduction in IP6 levels without altering cell viability (Frederick et al, 2005), we used CRISPR/Cas9 to remove IPMK from human 293T cells (Figure S1A)
Summary
The HIV-1 capsid undergoes a number of transformations during viral replication: assembly, maturation, host interaction, and uncoating. The molecular mechanisms that drive assembly of the immature and mature lattices during production and that trigger capsid uncoating during infection remain unclear Understanding these processes is complicated by the conflicting structural requirements imposed by capsid function: the capsid may need to be stable for many hours inside the cell (Holmes et al, 2015) yet undergo rapid disassembly in the right place and at the right time. Definitions of even these fundamental parameters remain controversial, and there is no consensus about exactly what uncoating means and when and where it happens
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