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Article ; Online: Membraneless organelles restructured and built by pandemic viruses: HIV-1 and SARS-CoV-2.

Scoca, Viviana / Di Nunzio, Francesca

2021 Volume 13, Issue 4, Page(s) 259–268

Abstract: Viruses hijack host functions to invade their target cells and spread to new cells. Specifically, viruses learned to usurp liquid‒liquid phase separation (LLPS), a newly exploited mechanism, used by the cell to concentrate enzymes to accelerate and ... ...

Abstract	Viruses hijack host functions to invade their target cells and spread to new cells. Specifically, viruses learned to usurp liquid‒liquid phase separation (LLPS), a newly exploited mechanism, used by the cell to concentrate enzymes to accelerate and confine a wide variety of cellular processes. LLPS gives rise to actual membraneless organelles (MLOs), which do not only increase reaction rates but also act as a filter to select molecules to be retained or to be excluded from the liquid droplet. This is exactly what seems to happen with the condensation of SARS-CoV-2 nucleocapsid protein to favor the packaging of intact viral genomes, excluding viral subgenomic or host cellular RNAs. Another older pandemic virus, HIV-1, also takes advantage of LLPS in the host cell during the viral cycle. Recent discoveries highlighted that HIV-1 RNA genome condensates in nuclear MLOs accompanied by specific host and viral proteins, breaking the dogma of retroviruses that limited viral synthesis exclusively to the cytoplasmic compartment. Intriguing fundamental properties of viral/host LLPS remain still unclear. Future studies will contribute to deeply understanding the role of pathogen-induced MLOs in the epidemic invasion of pandemic viruses.
MeSH term(s)	COVID-19/pathology ; COVID-19/virology ; HIV Infections/pathology ; HIV Infections/virology ; HIV-1/genetics ; HIV-1/isolation & purification ; HIV-1/physiology ; Host-Pathogen Interactions ; Humans ; Nucleocapsid Proteins/metabolism ; Organelles/metabolism ; RNA, Viral/metabolism ; SARS-CoV-2/genetics ; SARS-CoV-2/isolation & purification ; SARS-CoV-2/physiology ; Virus Replication
Chemical Substances	Nucleocapsid Proteins ; RNA, Viral
Language	English
Publishing date	2021-03-24
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2500949-7
ISSN	1759-4685 ; 1759-4685
ISSN (online)	1759-4685
ISSN	1759-4685
DOI	10.1093/jmcb/mjab020
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: The HIV-1 Capsid: From Structural Component to Key Factor for Host Nuclear Invasion.

Scoca, Viviana / Di Nunzio, Francesca

Viruses

2021 Volume 13, Issue 2

Abstract: Since the discovery of HIV-1, the viral capsid has been recognized to have an important role as a structural protein that holds the viral genome, together with viral proteins essential for viral life cycle, such as the reverse transcriptase (RT) and the ... ...

Abstract	Since the discovery of HIV-1, the viral capsid has been recognized to have an important role as a structural protein that holds the viral genome, together with viral proteins essential for viral life cycle, such as the reverse transcriptase (RT) and the integrase (IN). The reverse transcription process takes place between the cytoplasm and the nucleus of the host cell, thus the Reverse Transcription Complexes (RTCs)/Pre-integration Complexes (PICs) are hosted in intact or partial cores. Early biochemical assays failed to identify the viral CA associated to the RTC/PIC, possibly due to the stringent detergent conditions used to fractionate the cells or to isolate the viral complexes. More recently, it has been observed that some host partners of capsid, such as Nup153 and CPSF6, can only bind multimeric CA proteins organized in hexamers. Those host factors are mainly located in the nuclear compartment, suggesting the entrance of the viral CA as multimeric structure inside the nucleus. Recent data show CA complexes within the nucleus having a different morphology from the cytoplasmic ones, clearly highlighting the remodeling of the viral cores during nuclear translocation. Thus, the multimeric CA complexes lead the viral genome into the host nuclear compartment, piloting the intranuclear journey of HIV-1 in order to successfully replicate. The aim of this review is to discuss and analyze the main discoveries to date that uncover the viral capsid as a key player in the reverse transcription and PIC maturation until the viral DNA integration into the host genome.
MeSH term(s)	Active Transport, Cell Nucleus ; Capsid/chemistry ; Capsid/metabolism ; Capsid Proteins/chemistry ; Capsid Proteins/metabolism ; Cell Nucleus/metabolism ; Cell Nucleus/virology ; HIV-1/chemistry ; HIV-1/metabolism ; HIV-1/physiology ; Models, Biological ; Nuclear Pore Complex Proteins/metabolism ; Reverse Transcription ; Virus Integration ; Virus Replication
Chemical Substances	Capsid Proteins ; Nuclear Pore Complex Proteins
Language	English
Publishing date	2021-02-10
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2516098-9
ISSN	1999-4915 ; 1999-4915
ISSN (online)	1999-4915
ISSN	1999-4915
DOI	10.3390/v13020273
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Article ; Online: HIV-induced membraneless organelles orchestrate post-nuclear entry steps.

Scoca, Viviana / Morin, Renaud / Collard, Maxence / Tinevez, Jean-Yves / Di Nunzio, Francesca

Journal of molecular cell biology

2022 Volume 14, Issue 11

Abstract: HIV integration occurs in chromatin sites that favor the release of high levels of viral progeny; alternatively, the virus is also able to discreetly coexist with the host. The viral infection perturbs the cellular environment inducing the remodelling of ...

Abstract	HIV integration occurs in chromatin sites that favor the release of high levels of viral progeny; alternatively, the virus is also able to discreetly coexist with the host. The viral infection perturbs the cellular environment inducing the remodelling of the nuclear landscape. Indeed, HIV-1 triggers the nuclear clustering of the host factor CPSF6, but the underlying mechanism is poorly understood. Our data indicate that HIV usurps a recently discovered biological phenomenon, called liquid-liquid phase separation, to hijack the host cell. We observed CPSF6 clusters as part of HIV-induced membraneless organelles (HIV-1 MLOs) in macrophages, one of the main HIV target cell types. We describe that HIV-1 MLOs follow phase-separation rules and represent functional biomolecular condensates. We highlight HIV-1 MLOs as hubs of nuclear reverse transcription, while the double-stranded viral DNA, once formed, rapidly migrates outside these structures. Transcription-competent proviruses localize outside but near HIV-1 MLOs in LEDGF-abundant regions, known to be active chromatin sites. Therefore, HIV-1 MLOs orchestrate viral events prior to the integration step and create a favorable environment for the viral replication. This study uncovers single functional host-viral complexes in their nuclear landscape, which is markedly restructured by HIV-1.
MeSH term(s)	Humans ; Biomolecular Condensates ; Cell Nucleus/metabolism ; Chromatin/metabolism ; HIV Infections ; Virus Replication
Chemical Substances	Chromatin
Language	English
Publishing date	2022-10-29
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2500949-7
ISSN	1759-4685 ; 1759-4685
ISSN (online)	1759-4685
ISSN	1759-4685
DOI	10.1093/jmcb/mjac060
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Article ; Online: Clustering and reverse transcription of HIV-1 genomes in nuclear niches of macrophages.

Rensen, Elena / Mueller, Florian / Scoca, Viviana / Parmar, Jyotsana J / Souque, Philippe / Zimmer, Christophe / Di Nunzio, Francesca

The EMBO journal

2020 Volume 40, Issue 1, Page(s) e105247

Abstract: In order to replicate, human immunodeficiency virus (HIV-1) reverse-transcribes its RNA genome into DNA, which subsequently integrates into host cell chromosomes. These two key events of the viral life cycle are commonly viewed as separate not only in ... ...

Abstract	In order to replicate, human immunodeficiency virus (HIV-1) reverse-transcribes its RNA genome into DNA, which subsequently integrates into host cell chromosomes. These two key events of the viral life cycle are commonly viewed as separate not only in time, but also in cellular space, since reverse transcription (RT) is thought to be completed in the cytoplasm before nuclear import and integration. However, the spatiotemporal organization of the early viral replication cycle in macrophages, the natural non-dividing target cells that constitute reservoirs of HIV-1 and an obstacle to curing AIDS, remains unclear. Here, we demonstrate that infected macrophages display large nuclear foci of viral DNA (vDNA) and viral RNA, in which multiple viral genomes cluster together. These clusters form in the absence of chromosomal integration, sequester the paraspeckle protein CPSF6, and localize to nuclear speckles. Surprisingly, these viral RNA clusters consist mostly of genomic, incoming RNA, both in cells where reverse transcription is pharmacologically suppressed and in untreated cells. We demonstrate that following temporary inhibition, reverse transcription can resume in the nucleus and lead to vDNA accumulation in these clusters. We further show that nuclear reverse transcription can result in transcription-competent viral DNA. These findings change our understanding of the early HIV-1 replication cycle and may have implications for addressing HIV-1 persistence.
MeSH term(s)	Active Transport, Cell Nucleus/genetics ; Cell Line ; Cell Nucleus/virology ; Cluster Analysis ; Cytoplasm/virology ; DNA, Viral/genetics ; Genome, Viral/genetics ; HEK293 Cells ; HIV Infections/virology ; HIV-1/genetics ; Humans ; Macrophages/virology ; RNA, Viral/genetics ; Reverse Transcription/genetics ; THP-1 Cells ; Virus Replication/genetics
Chemical Substances	DNA, Viral ; RNA, Viral
Language	English
Publishing date	2020-12-03
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	586044-1
ISSN	1460-2075 ; 0261-4189
ISSN (online)	1460-2075
ISSN	0261-4189
DOI	10.15252/embj.2020105247
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Article ; Online: Cyclophilin A Prevents HIV-1 Restriction in Lymphocytes by Blocking Human TRIM5α Binding to the Viral Core.

Selyutina, Anastasia / Persaud, Mirjana / Simons, Lacy M / Bulnes-Ramos, Angel / Buffone, Cindy / Martinez-Lopez, Alicia / Scoca, Viviana / Di Nunzio, Francesca / Hiatt, Joseph / Marson, Alexander / Krogan, Nevan J / Hultquist, Judd F / Diaz-Griffero, Felipe

Cell reports

2020 Volume 30, Issue 11, Page(s) 3766–3777.e6

Abstract: Disruption of cyclophilin A (CypA)-capsid interactions affects HIV-1 replication in human lymphocytes. To understand this mechanism, we utilize human Jurkat cells, peripheral blood mononuclear cells (PBMCs), and ... ...

Abstract	Disruption of cyclophilin A (CypA)-capsid interactions affects HIV-1 replication in human lymphocytes. To understand this mechanism, we utilize human Jurkat cells, peripheral blood mononuclear cells (PBMCs), and CD4
MeSH term(s)	Adult ; Antiviral Restriction Factors ; CD4-Positive T-Lymphocytes/drug effects ; CD4-Positive T-Lymphocytes/immunology ; CD4-Positive T-Lymphocytes/virology ; Capsid/metabolism ; Cell Line ; Cyclophilin A/metabolism ; Cyclosporine/pharmacology ; HIV Infections/metabolism ; HIV Infections/virology ; HIV-1/drug effects ; HIV-1/genetics ; HIV-1/physiology ; Humans ; Lymphocytes/drug effects ; Lymphocytes/metabolism ; Lymphocytes/virology ; Mutation/genetics ; Protein Binding/drug effects ; Reverse Transcription/drug effects ; Reverse Transcription/genetics ; Tripartite Motif Proteins/metabolism ; Ubiquitin-Protein Ligases/metabolism
Chemical Substances	Antiviral Restriction Factors ; Tripartite Motif Proteins ; Cyclosporine (83HN0GTJ6D) ; TRIM5 protein, human (EC 2.3.2.27) ; Ubiquitin-Protein Ligases (EC 2.3.2.27) ; Cyclophilin A (EC 5.2.1.-)
Language	English
Publishing date	2020-03-17
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2020.02.100
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Article ; Online: Remodeling of the Core Leads HIV-1 Preintegration Complex into the Nucleus of Human Lymphocytes.

Blanco-Rodriguez, Guillermo / Gazi, Anastasia / Monel, Blandine / Frabetti, Stella / Scoca, Viviana / Mueller, Florian / Schwartz, Olivier / Krijnse-Locker, Jacomine / Charneau, Pierre / Di Nunzio, Francesca

Journal of virology

2020 Volume 94, Issue 11

Abstract: Retroviral replication proceeds through obligate integration of the viral DNA into the host genome. In particular, for the HIV-1 genome to enter the nucleus, it must be led through the nuclear pore complex (NPC). During the HIV-1 cytoplasmic journey, the ...

Abstract	Retroviral replication proceeds through obligate integration of the viral DNA into the host genome. In particular, for the HIV-1 genome to enter the nucleus, it must be led through the nuclear pore complex (NPC). During the HIV-1 cytoplasmic journey, the viral core acts as a shell to protect the viral genetic material from antiviral sensors and ensure an adequate environment for reverse transcription. However, the relatively narrow size of the nuclear pore channel requires that the HIV-1 core is reshaped into a structure that fits the pore. On the other hand, the organization of the viral CA proteins that remain associated with the preintegration complex (PIC) during and after nuclear translocation is still enigmatic. In this study, we analyzed the progressive organizational changes of viral CA proteins within the cytoplasm and the nucleus by immunogold labeling. Furthermore, we set up a novel technology, HIV-1 ANCHOR, which enables the specific detection of the retrotranscribed DNA by fluorescence microscopy, thereby offering the opportunity to uncover the architecture of the potential HIV-1 PIC. Thus, we combined the immunoelectron microscopy and ANCHOR technologies to reveal the presence of DNA- and CA-positive complexes by correlated light and electron microscopy (CLEM). During and after nuclear translocation, HIV-1 appears as a complex of viral DNA decorated by multiple viral CA proteins remodeled in a pearl necklace-like shape. Thus, we could describe how CA proteins are reshaped around the viral DNA to permit the entrance of the HIV-1 in the nucleus. This particular CA protein complex composed of the integrase and the retrotranscribed DNA leads the HIV-1 genome inside the host nucleus. Our findings contribute to the understanding of the early steps of HIV-1 infection and provide new insights into the organization of HIV-1 CA proteins during and after viral nuclear entry. Of note, we are now able to visualize the viral DNA in viral complexes, opening up new perspectives for future studies on virus's fate in the cell nucleus.
MeSH term(s)	Active Transport, Cell Nucleus ; CD4-Positive T-Lymphocytes/metabolism ; CD4-Positive T-Lymphocytes/virology ; Cell Nucleus/genetics ; Cell Nucleus/metabolism ; Cell Nucleus/virology ; HEK293 Cells ; HIV Infections/genetics ; HIV Infections/metabolism ; HIV Integrase/genetics ; HIV Integrase/metabolism ; HIV-1/genetics ; HIV-1/metabolism ; HeLa Cells ; Humans ; Multiprotein Complexes/genetics ; Multiprotein Complexes/metabolism ; Virus Integration
Chemical Substances	Multiprotein Complexes ; HIV Integrase (EC 2.7.7.-)
Language	English
Publishing date	2020-05-18
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/JVI.00135-20
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Article ; Online: Cyclophilin A Prevents HIV-1 Restriction in Lymphocytes by Blocking Human TRIM5α Binding to the Viral Core

Anastasia Selyutina / Mirjana Persaud / Lacy M. Simons / Angel Bulnes-Ramos / Cindy Buffone / Alicia Martinez-Lopez / Viviana Scoca / Francesca Di Nunzio / Joseph Hiatt / Alexander Marson / Nevan J. Krogan / Judd F. Hultquist / Felipe Diaz-Griffero

Cell Reports, Vol 30, Iss 11, Pp 3766-3777.e

2020 Volume 6

Abstract: Summary: Disruption of cyclophilin A (CypA)-capsid interactions affects HIV-1 replication in human lymphocytes. To understand this mechanism, we utilize human Jurkat cells, peripheral blood mononuclear cells (PBMCs), and CD4+ T cells. Our results show ... ...

Abstract	Summary: Disruption of cyclophilin A (CypA)-capsid interactions affects HIV-1 replication in human lymphocytes. To understand this mechanism, we utilize human Jurkat cells, peripheral blood mononuclear cells (PBMCs), and CD4+ T cells. Our results show that inhibition of HIV-1 infection caused by disrupting CypA-capsid interactions is dependent on human tripartite motif 5α (TRIM5αhu), showing that TRIM5αhu restricts HIV-1 in CD4+ T cells. Accordingly, depletion of TRIM5αhu in CD4+ T cells rescues HIV-1 that fail to interact with CypA, such as HIV-1-P90A. We found that TRIM5αhu binds to the HIV-1 core. Disruption of CypA-capsid interactions fail to affect HIV-1-A92E/G94D infection, correlating with the loss of TRIM5αhu binding to HIV-1-A92E/G94D cores. Disruption of CypA-capsid interactions in primary cells has a greater inhibitory effect on HIV-1 when compared to Jurkat cells. Consistent with TRIM5α restriction, disruption of CypA-capsid interactions in CD4+ T cells inhibits reverse transcription. Overall, our results reveal that CypA binding to the core protects HIV-1 from TRIM5αhu restriction. : Selyutina et al. show that, during HIV infection, the drug cyclosporine removes cyclophilin A bound to the HIV-1 core, facilitating the interaction between human TRIM5α and the core. This inhibits infection and explains the mechanism behind the long-standing observation that cyclosporine counteracts HIV. Keywords: HIV-1, CypA, TRIM5αhu, core, capsid, restriction, CD4+ T cells, cyclosporine A, reverse transcription, uncoating
Keywords	Biology (General) ; QH301-705.5
Subject code	570
Language	English
Publishing date	2020-03-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
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Article: Remodeling of the Core Leads HIV-1 Preintegration Complex into the Nucleus of Human Lymphocytes

Gazi, Anastasia / Monel, Blandine / Scoca, Viviana / SCHWARTZ, OLIVIER / Krijnse Locker, Jacomina / CHARNEAU, Pierre / Di Nunzio, Francesca

Journal of virology, 94:e00135-20

2020

Institution	Paul-Ehrlich-Institut
Abstract	Retroviral replication proceeds through obligate integration of the viral DNA into the host genome. In particular, for the HIV-1 genome to enter the nucleus, it must be led through the nuclear pore complex (NPC). During the HIV-1 cytoplasmic journey, the viral core acts as a shell to protect the viral genetic material from antiviral sensors and ensure an adequate environment for reverse transcription. However, the relatively narrow size of the nuclear pore channel requires that the HIV-1 core is reshaped into a structure that fits the pore. On the other hand, the organization of the viral CA proteins that remain associated with the preintegration complex (PIC) during and after nuclear translocation is still enigmatic. In this study, we analyzed the progressive organizational changes of viral CA proteins within the cytoplasm and the nucleus by immunogold labeling. Furthermore, we set up a novel technology, HIV-1 ANCHOR, which enables the specific detection of the retrotranscribed DNA by fluorescence microscopy, thereby offering the opportunity to uncover the architecture of the potential HIV-1 PIC. Thus, we combined the immunoelectron microscopy and ANCHOR technologies to reveal the presence of DNA- and CA-positive complexes by correlated light and electron microscopy (CLEM). During and after nuclear translocation, HIV-1 appears as a complex of viral DNA decorated by multiple viral CA proteins remodeled in a pearl necklace-like shape. Thus, we could describe how CA proteins are reshaped around the viral DNA to permit the entrance of the HIV-1 in the nucleus. This particular CA protein complex composed of the integrase and the retrotranscribed DNA leads the HIV-1 genome inside the host nucleus. Our findings contribute to the understanding of the early steps of HIV-1 infection and provide new insights into the organization of HIV-1 CA proteins during and after viral nuclear entry. Of note, we are now able to visualize the viral DNA in viral complexes, opening up new perspectives for future studies on virus’s fate in the cell nucleus.
Keywords	HIV-Infektion <Motiv> ; human immunodeficiency virus ; nuclear import/export ; integration ; viral replication
Language	English
Document type	Article
Database	Repository for Life Sciences

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Article ; Online: Membraneless organelles restructured and built by pandemic viruses: HIV-1 and SARS-CoV-2.

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Article ; Online: The HIV-1 Capsid: From Structural Component to Key Factor for Host Nuclear Invasion.

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Article ; Online: HIV-induced membraneless organelles orchestrate post-nuclear entry steps.

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Article ; Online: Clustering and reverse transcription of HIV-1 genomes in nuclear niches of macrophages.

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Article ; Online: Cyclophilin A Prevents HIV-1 Restriction in Lymphocytes by Blocking Human TRIM5α Binding to the Viral Core.

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Article ; Online: Remodeling of the Core Leads HIV-1 Preintegration Complex into the Nucleus of Human Lymphocytes.

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In stock of ZB MED Cologne/Königswinter

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Article ; Online: Cyclophilin A Prevents HIV-1 Restriction in Lymphocytes by Blocking Human TRIM5α Binding to the Viral Core

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Article: Remodeling of the Core Leads HIV-1 Preintegration Complex into the Nucleus of Human Lymphocytes

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