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Atomic-scale characterization of mature HIV-1 capsid stabilization by inositol hexakisphosphate (IP6).

ABSTRACT: Inositol hexakisphosphates (IP6) are cellular cofactors that promote the assembly of mature capsids of HIV. These negatively charged molecules coordinate an electropositive ring of arginines at the center of pores distributed throughout the capsid surface. Kinetic studies indicate that the binding of IP6 increases the stable lifetimes of the capsid by several orders of magnitude from minutes to hours. Using all-atom molecular dynamics simulations, we uncover the mechanisms that underlie the unusually high stability of mature capsids in complex with IP6 We find that capsid hexamers and pentamers have differential binding modes for IP6 Ligand density calculations show three sites of interaction with IP6 including at a known capsid inhibitor binding pocket. Free energy calculations demonstrate that IP6 preferentially stabilizes pentamers over hexamers to enhance fullerene modes of assembly. These results elucidate the molecular role of IP6 in stabilizing and assembling the retroviral capsid.

SUBMITTER: Yu A

PROVIDER: S-EPMC7494349 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Atomic-scale characterization of mature HIV-1 capsid stabilization by inositol hexakisphosphate (IP6).

Yu Alvin A Lee Elizabeth M Y EMY Jin Jaehyeok J Voth Gregory A GA

Science advances 20200916 38

Inositol hexakisphosphates (IP6) are cellular cofactors that promote the assembly of mature capsids of HIV. These negatively charged molecules coordinate an electropositive ring of arginines at the center of pores distributed throughout the capsid surface. Kinetic studies indicate that the binding of IP6 increases the stable lifetimes of the capsid by several orders of magnitude from minutes to hours. Using all-atom molecular dynamics simulations, we uncover the mechanisms ...[more]

PMID: 32938668

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Project description:Inositol hexakisphosphate (IP6) potently stimulates HIV-1 particle assembly in vitro and infectious particle production in vivo. However, knockout cells lacking inositol-pentakisphosphate 2-kinase (IPPK-KO), the enzyme that produces IP6 by phosphorylation of inositol pentakisphosphate (IP5), were still able to produce infectious HIV-1 particles at a greatly reduced rate. HIV-1 in vitro assembly can also be stimulated to a lesser extent with IP5, but until recently, it was not known if IP5 could also function in promoting assembly in vivo. Here we addressed whether there is an absolute requirement for IP6 or IP5 in the production of infectious HIV-1 particles. IPPK-KO cells expressed no detectable IP6 but elevated IP5 levels and displayed a 20-100-fold reduction in infectious particle production, correlating with lost virus release. Transient transfection of an IPPK expression vector stimulated infectious particle production and release in IPPK-KO but not wildtype cells. Several attempts to make IP6/IP5 deficient stable cells were not successful, but transient expression of the enzyme multiple inositol polyphosphate phosphatase-1 (MINPP1) into IPPK-KOs resulted in near ablation of IP6 and IP5. Under these conditions, we found that HIV-1 infectious particle production and virus release were essentially abolished (1000-fold reduction) demonstrating an IP6/IP5 requirement. However, other retroviruses including a Gammaretrovirus, a Betaretrovirus, and two non-primate Lentiviruses displayed only a modest (3-fold) reduction in infectious particle production from IPPK-KOs and were not significantly altered by expression of IPPK or MINPP1. The only other retrovirus found to show a clear IP6/IP5 dependence was the primate (macaque) Lentivirus Simian Immunodeficiency Virus, which displayed similar sensitivity as HIV-1. We were not able to determine if producer cell IP6/IP5 is required at additional steps beyond assembly because viral particles devoid of both molecules could not be generated. Finally, we found that loss of IP6/IP5 in viral target cells had no effect on permissivity to HIV-1 infection.

Dataset Information

Atomic-scale characterization of mature HIV-1 capsid stabilization by inositol hexakisphosphate (IP6).

Publications

Atomic-scale characterization of mature HIV-1 capsid stabilization by inositol hexakisphosphate (IP<sub>6</sub>).

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