HIV-1 capsids mimic a microtubule regulator to coordinate early stages of infection

Eveline Santos da Silva; Shanmugapriya Shanmugapriya; Viacheslav Malikov; Feng Gu; M. Keegan Delaney; Mojgan H. Naghavi

doi:10.15252/embj.2020104870

HIV-1 capsids mimic a microtubule regulator to coordinate early stages of infection

Eveline Santos da Silva, Shanmugapriya Shanmugapriya, Viacheslav Malikov, Feng Gu, M. Keegan Delaney, Mojgan H. Naghavi^*

^*Corresponding author for this work

Microbiology-Immunology

Research output: Contribution to journal › Article › peer-review

24 Scopus citations

Abstract

While the microtubule end-binding protein, EB1 facilitates early stages of HIV-1 infection, how it does so remains unclear. Here, we show that beyond its effects on microtubule acetylation, EB1 also indirectly contributes to infection by delivering the plus-end tracking protein (+TIP), cytoplasmic linker protein 170 (CLIP170) to the cell periphery. CLIP170 bound to intact HIV-1 cores or in vitro assembled capsid–nucleocapsid complexes, while EB1 did not. Moreover, unlike EB1 and several other +TIPs, CLIP170 enhanced infection independently of effects on microtubule acetylation. Capsid mutants and imaging revealed that CLIP170 bound HIV-1 cores in a manner distinct from currently known capsid cofactors, influenced by pentamer composition or curvature. Structural analyses revealed an EB-like +TIP-binding motif within the capsid major homology region (MHR) that binds SxIP motifs found in several +TIPs, and variability across this MHR sequence correlated with the extent to which different retroviruses engage CLIP170 to facilitate infection. Our findings provide mechanistic insights into the complex roles of +TIPs in mediating early stages of retroviral infection, and reveal divergent capsid-based EB1 mimicry across retroviral species.

Original language	English (US)
Article number	e104870
Journal	EMBO Journal
Volume	39
Issue number	20
DOIs	https://doi.org/10.15252/embj.2020104870
State	Published - Oct 15 2020

Funding

We are grateful to Derek Walsh, Barbie Ganser‐Pornillos, and Owen Pornillos for reagents and advice. We also thank Gregg Gundersen, Thomas Hope, Gregory Melikian, Vladimir Rodionov, and Vladimir Jovasevic for reagents. We thank Kayla Schipper and Amy Hulme, for technical assistance. The following reagents were obtained through the NIH AIDS Research and Reference Reagent Program, Division of AIDS, NIAID, NIH: pNL4‐3.Luc.R. .E from Dr. Nathaniel Landau, and HIV‐1 p24 (AG3.0) antibody from Dr. Jonathan Allan. This work was supported by NIH grant P01GM105536, and R01AI150559 (to M.H.N.), and NIH Grant T32AI007476‐19 (to M.K.D.). − − We are grateful to Derek Walsh, Barbie Ganser-Pornillos, and Owen Pornillos for reagents and advice. We also thank Gregg Gundersen, Thomas Hope, Gregory Melikian, Vladimir Rodionov, and Vladimir Jovasevic for reagents. We thank Kayla Schipper and Amy Hulme, for technical assistance. The following reagents were obtained through the NIH AIDS Research and Reference Reagent Program, Division of AIDS, NIAID, NIH: pNL4-3.Luc.R. ?.E? from Dr. Nathaniel Landau, and HIV-1 p24 (AG3.0) antibody from Dr. Jonathan Allan. This work was supported by NIH grant P01GM105536, and R01AI150559 (to M.H.N.), and NIH Grant T32AI007476-19 (to M.K.D.).

Keywords

+TIP
CLIP170
HIV-1
trafficking
uncoating

ASJC Scopus subject areas

General Neuroscience
Molecular Biology
General Biochemistry, Genetics and Molecular Biology
General Immunology and Microbiology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.15252/embj.2020104870

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title = "HIV-1 capsids mimic a microtubule regulator to coordinate early stages of infection",

abstract = "While the microtubule end-binding protein, EB1 facilitates early stages of HIV-1 infection, how it does so remains unclear. Here, we show that beyond its effects on microtubule acetylation, EB1 also indirectly contributes to infection by delivering the plus-end tracking protein (+TIP), cytoplasmic linker protein 170 (CLIP170) to the cell periphery. CLIP170 bound to intact HIV-1 cores or in vitro assembled capsid–nucleocapsid complexes, while EB1 did not. Moreover, unlike EB1 and several other +TIPs, CLIP170 enhanced infection independently of effects on microtubule acetylation. Capsid mutants and imaging revealed that CLIP170 bound HIV-1 cores in a manner distinct from currently known capsid cofactors, influenced by pentamer composition or curvature. Structural analyses revealed an EB-like +TIP-binding motif within the capsid major homology region (MHR) that binds SxIP motifs found in several +TIPs, and variability across this MHR sequence correlated with the extent to which different retroviruses engage CLIP170 to facilitate infection. Our findings provide mechanistic insights into the complex roles of +TIPs in mediating early stages of retroviral infection, and reveal divergent capsid-based EB1 mimicry across retroviral species.",

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author = "{Santos da Silva}, Eveline and Shanmugapriya Shanmugapriya and Viacheslav Malikov and Feng Gu and Delaney, {M. Keegan} and Naghavi, {Mojgan H.}",

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AU - Naghavi, Mojgan H.

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AB - While the microtubule end-binding protein, EB1 facilitates early stages of HIV-1 infection, how it does so remains unclear. Here, we show that beyond its effects on microtubule acetylation, EB1 also indirectly contributes to infection by delivering the plus-end tracking protein (+TIP), cytoplasmic linker protein 170 (CLIP170) to the cell periphery. CLIP170 bound to intact HIV-1 cores or in vitro assembled capsid–nucleocapsid complexes, while EB1 did not. Moreover, unlike EB1 and several other +TIPs, CLIP170 enhanced infection independently of effects on microtubule acetylation. Capsid mutants and imaging revealed that CLIP170 bound HIV-1 cores in a manner distinct from currently known capsid cofactors, influenced by pentamer composition or curvature. Structural analyses revealed an EB-like +TIP-binding motif within the capsid major homology region (MHR) that binds SxIP motifs found in several +TIPs, and variability across this MHR sequence correlated with the extent to which different retroviruses engage CLIP170 to facilitate infection. Our findings provide mechanistic insights into the complex roles of +TIPs in mediating early stages of retroviral infection, and reveal divergent capsid-based EB1 mimicry across retroviral species.

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HIV-1 capsids mimic a microtubule regulator to coordinate early stages of infection

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Keywords

ASJC Scopus subject areas

UN SDGs

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