Rhesus TRIM5α disrupts the HIV-1 capsid at the inter-hexamer interfaces.

TRIM proteins play important roles in the innate immune defense against retroviral infection, including human immunodeficiency virus type-1 (HIV-1). Rhesus macaque TRIM5α (TRIM5α(rh)) targets the HIV-1 capsid and blocks infection at an early post-entry stage, prior to reverse transcription. Studies...

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Autores principales:	Gongpu Zhao, Danxia Ke, Thomas Vu, Jinwoo Ahn, Vaibhav B Shah, Ruifeng Yang, Christopher Aiken, Lisa M Charlton, Angela M Gronenborn, Peijun Zhang
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/fdf7626b6bc34083ba2352640dadd6bb
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spelling	oai:doaj.org-article:fdf7626b6bc34083ba2352640dadd6bb2021-11-18T06:03:30ZRhesus TRIM5α disrupts the HIV-1 capsid at the inter-hexamer interfaces.1553-73661553-737410.1371/journal.ppat.1002009https://doaj.org/article/fdf7626b6bc34083ba2352640dadd6bb2011-03-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21455494/pdf/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374TRIM proteins play important roles in the innate immune defense against retroviral infection, including human immunodeficiency virus type-1 (HIV-1). Rhesus macaque TRIM5α (TRIM5α(rh)) targets the HIV-1 capsid and blocks infection at an early post-entry stage, prior to reverse transcription. Studies have shown that binding of TRIM5α to the assembled capsid is essential for restriction and requires the coiled-coil and B30.2/SPRY domains, but the molecular mechanism of restriction is not fully understood. In this study, we investigated, by cryoEM combined with mutagenesis and chemical cross-linking, the direct interactions between HIV-1 capsid protein (CA) assemblies and purified TRIM5α(rh) containing coiled-coil and SPRY domains (CC-SPRY(rh)). Concentration-dependent binding of CC-SPRY(rh) to CA assemblies was observed, while under equivalent conditions the human protein did not bind. Importantly, CC-SPRY(rh), but not its human counterpart, disrupted CA tubes in a non-random fashion, releasing fragments of protofilaments consisting of CA hexamers without dissociation into monomers. Furthermore, such structural destruction was prevented by inter-hexamer crosslinking using P207C/T216C mutant CA with disulfide bonds at the CTD-CTD trimer interface of capsid assemblies, but not by intra-hexamer crosslinking via A14C/E45C at the NTD-NTD interface. The same disruption effect by TRIM5α(rh) on the inter-hexamer interfaces also occurred with purified intact HIV-1 cores. These results provide insights concerning how TRIM5α disrupts the virion core and demonstrate that structural damage of the viral capsid by TRIM5α is likely one of the important components of the mechanism of TRIM5α-mediated HIV-1 restriction.Gongpu ZhaoDanxia KeThomas VuJinwoo AhnVaibhav B ShahRuifeng YangChristopher AikenLisa M CharltonAngela M GronenbornPeijun ZhangPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 7, Iss 3, p e1002009 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Gongpu Zhao Danxia Ke Thomas Vu Jinwoo Ahn Vaibhav B Shah Ruifeng Yang Christopher Aiken Lisa M Charlton Angela M Gronenborn Peijun Zhang Rhesus TRIM5α disrupts the HIV-1 capsid at the inter-hexamer interfaces.
description	TRIM proteins play important roles in the innate immune defense against retroviral infection, including human immunodeficiency virus type-1 (HIV-1). Rhesus macaque TRIM5α (TRIM5α(rh)) targets the HIV-1 capsid and blocks infection at an early post-entry stage, prior to reverse transcription. Studies have shown that binding of TRIM5α to the assembled capsid is essential for restriction and requires the coiled-coil and B30.2/SPRY domains, but the molecular mechanism of restriction is not fully understood. In this study, we investigated, by cryoEM combined with mutagenesis and chemical cross-linking, the direct interactions between HIV-1 capsid protein (CA) assemblies and purified TRIM5α(rh) containing coiled-coil and SPRY domains (CC-SPRY(rh)). Concentration-dependent binding of CC-SPRY(rh) to CA assemblies was observed, while under equivalent conditions the human protein did not bind. Importantly, CC-SPRY(rh), but not its human counterpart, disrupted CA tubes in a non-random fashion, releasing fragments of protofilaments consisting of CA hexamers without dissociation into monomers. Furthermore, such structural destruction was prevented by inter-hexamer crosslinking using P207C/T216C mutant CA with disulfide bonds at the CTD-CTD trimer interface of capsid assemblies, but not by intra-hexamer crosslinking via A14C/E45C at the NTD-NTD interface. The same disruption effect by TRIM5α(rh) on the inter-hexamer interfaces also occurred with purified intact HIV-1 cores. These results provide insights concerning how TRIM5α disrupts the virion core and demonstrate that structural damage of the viral capsid by TRIM5α is likely one of the important components of the mechanism of TRIM5α-mediated HIV-1 restriction.
format	article
author	Gongpu Zhao Danxia Ke Thomas Vu Jinwoo Ahn Vaibhav B Shah Ruifeng Yang Christopher Aiken Lisa M Charlton Angela M Gronenborn Peijun Zhang
author_facet	Gongpu Zhao Danxia Ke Thomas Vu Jinwoo Ahn Vaibhav B Shah Ruifeng Yang Christopher Aiken Lisa M Charlton Angela M Gronenborn Peijun Zhang
author_sort	Gongpu Zhao
title	Rhesus TRIM5α disrupts the HIV-1 capsid at the inter-hexamer interfaces.
title_short	Rhesus TRIM5α disrupts the HIV-1 capsid at the inter-hexamer interfaces.
title_full	Rhesus TRIM5α disrupts the HIV-1 capsid at the inter-hexamer interfaces.
title_fullStr	Rhesus TRIM5α disrupts the HIV-1 capsid at the inter-hexamer interfaces.
title_full_unstemmed	Rhesus TRIM5α disrupts the HIV-1 capsid at the inter-hexamer interfaces.
title_sort	rhesus trim5α disrupts the hiv-1 capsid at the inter-hexamer interfaces.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/fdf7626b6bc34083ba2352640dadd6bb
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Rhesus TRIM5α disrupts the HIV-1 capsid at the inter-hexamer interfaces.

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