HIV integration occurs in chromatin sites that favor the release of high levels of viral progeny;alternatively, the virus is alsoable to discreetly coexist with the host. The viral infection perturbs the cellular envi...HIV integration occurs in chromatin sites that favor the release of high levels of viral progeny;alternatively, the virus is alsoable to discreetly coexist with the host. The viral infection perturbs the cellular environment inducing the remodelling of thenuclear landscape. Indeed, HIV-1 triggers the nuclear clustering of the host factor CPSF6, but the underlying mechanism ispoorly understood. Our data indicate that HIV usurps a recently discovered biological phenomenon, called liquid–liquid phaseseparation, to hijack the host cell. We observed CPSF6 clusters as part of HIV-induced membraneless organelles (HIV-1 MLOs) inmacrophages, one of the main HIV target cell types. We describe that HIV-1 MLOs follow phase-separation rules and representfunctional biomolecular condensates. We highlight HIV-1 MLOs as hubs of nuclear reverse transcription, while the double-strandedviral DNA, once formed, rapidly migrates outside these structures. Transcription-competent proviruses localize outside but nearHIV-1 MLOs in LEDGF-abundant regions, known to be active chromatin sites. Therefore, HIV-1 MLOs orchestrate viral events priorto the integration step and create a favorable environment for the viral replication. This study uncovers single functional host–viralcomplexes in their nuclear landscape, which is markedly restructured by HIV-1.展开更多
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...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.展开更多
基金funded by the ANRS REACTing grant(ECTZ88162)with a nominative PhD student fellowship(ECTZ88177)for V.S.the Sidaction/Fondation pour la Recherche Médicale(FRM)grant(VIH20170718001)Institut Pasteur.
文摘HIV integration occurs in chromatin sites that favor the release of high levels of viral progeny;alternatively, the virus is alsoable to discreetly coexist with the host. The viral infection perturbs the cellular environment inducing the remodelling of thenuclear landscape. Indeed, HIV-1 triggers the nuclear clustering of the host factor CPSF6, but the underlying mechanism ispoorly understood. Our data indicate that HIV usurps a recently discovered biological phenomenon, called liquid–liquid phaseseparation, to hijack the host cell. We observed CPSF6 clusters as part of HIV-induced membraneless organelles (HIV-1 MLOs) inmacrophages, one of the main HIV target cell types. We describe that HIV-1 MLOs follow phase-separation rules and representfunctional biomolecular condensates. We highlight HIV-1 MLOs as hubs of nuclear reverse transcription, while the double-strandedviral DNA, once formed, rapidly migrates outside these structures. Transcription-competent proviruses localize outside but nearHIV-1 MLOs in LEDGF-abundant regions, known to be active chromatin sites. Therefore, HIV-1 MLOs orchestrate viral events priorto the integration step and create a favorable environment for the viral replication. This study uncovers single functional host–viralcomplexes in their nuclear landscape, which is markedly restructured by HIV-1.
基金Work in the authors’laboratories was supported by the Agence Nationale de Recherche sur le SIDA(ANRS)/REACTing grant ECTZ88162 with a nominative PhD student fellowship ECTZ88177 for V.S.and by the Pasteur Institute.
文摘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.
