Modeling HIV-1 nuclear entry with nucleoporin-gated DNA-origami channels

Nature Structural & Molecular Biology, Journal Year: 2023, Volume and Issue: 30(4), P. 425 - 435

Published: Feb. 20, 2023

Language: Английский

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Two structural switches in HIV-1 capsid regulate capsid curvature and host factor binding

Proceedings of the National Academy of Sciences, Journal Year: 2023, Volume and Issue: 120(16)

Published: April 11, 2023

The mature HIV-1 capsid protects the viral genome and interacts with host proteins to travel from cell periphery into nucleus. To achieve this, protein, CA, constructs conical capsids a lattice of hexamers pentamers, engages in then relinquishes multiple interactions cellular an orchestrated fashion. Cellular factors including Nup153, CPSF6, Sec24C engage same pocket within CA hexamers. How assembles pentamers different curvatures, how oligomerization states or curvature might modulate host-protein interactions, binding cofactors single site is coordinated, all remain be elucidated. Here, using single-particle cryoEM, we have determined structure pentamer hexamer CA-IP

Language: Английский

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The capsid lattice engages a bipartite NUP153 motif to mediate nuclear entry of HIV-1 cores

Proceedings of the National Academy of Sciences, Journal Year: 2023, Volume and Issue: 120(13)

Published: March 21, 2023

Increasing evidence has suggested that the HIV-1 capsid enters nucleus in a largely assembled, intact form. However, not much is known about how cone-shaped interacts with nucleoporins (NUPs) nuclear pore for crossing complex. Here, we elucidate NUP153 binds by engaging assembled protein (CA) lattice. A bipartite motif containing both canonical and noncanonical interaction modules was identified at C-terminal tail region of NUP153. The cargo-targeting phenylalanine-glycine (FG) engaged CA hexamer. By contrast, previously unidentified triple-arginine (RRR) targeted tri-hexamer interface capsid. infection studies indicated FG- RRR-motifs were important import cores. Moreover, presence stabilized tubular assemblies vitro. Our results provide molecular-level mechanistic contributes to entry into nucleus.

Language: Английский

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Capsid–host interactions for HIV-1 ingress

Microbiology and Molecular Biology Reviews, Journal Year: 2023, Volume and Issue: 87(4)

Published: Sept. 26, 2023

The HIV-1 capsid, composed of approximately 1,200 copies the capsid protein, encases genomic RNA alongside viral nucleocapsid, reverse transcriptase, and integrase proteins. After cell entry, interacts with a myriad host factors to traverse cytoplasm, pass through nuclear pore complex (NPC), then traffic chromosomal sites for DNA integration. Integration may very well require dissolution but where when this uncoating event occurs remains hotly debated. Based on size constraints, long-prevailing view was that preceded transport, recent research has indicated remain largely intact during import, perhaps some structural remodeling required NPC traversal. Completion transcription in nucleus further aid uncoating. One canonical type factor, typified by CPSF6, leverages Phe-Gly (FG) motif bind capsid. Recent shown these peptides reside amid prion-like domains (PrLDs), which are stretches protein sequence devoid charged residues. Intermolecular PrLD interactions along exterior shell impart avid factor binding productive infection. Herein we overview capsid-host implicated ingress discuss important questions moving forward. Highlighting clinical relevance, long-acting ultrapotent inhibitor lenacapavir, engages same pocket as FG factors, recently approved treat people living HIV.

Language: Английский

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Elasticity of the HIV-1 core facilitates nuclear entry and infection

PLoS Pathogens, Journal Year: 2024, Volume and Issue: 20(9), P. e1012537 - e1012537

Published: Sept. 11, 2024

HIV-1 infection requires passage of the viral core through nuclear pore cell, a process that depends on functions capsid. Recent studies have shown cores enter nucleus prior to capsid disassembly. Interactions with complex are necessary but not sufficient for entry, and mechanism by which traverses comparably sized is unknown. Here we show highly elastic this property linked entry infectivity. Using atomic force microscopy-based approaches, found purified wild type rapidly returned their normal conical morphology following severe compression. Results from independently performed molecular dynamic simulations mature also revealed its property. Analysis four mutants exhibit impaired mutant brittle. Adaptation two viruses in cell culture resulted additional substitutions restored elasticity rescued infectivity entry. We capsid-targeting compound PF74 antiviral drug Lenacepavir reduce block at concentrations preserve interactions between envelope. Our results indicate fundamental enables thereby facilitating infection. These provide new insights into role mechanisms inhibitors.

Language: Английский

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Structural basis for nuclear import of hepatitis B virus (HBV) nucleocapsid core

Science Advances, Journal Year: 2024, Volume and Issue: 10(2)

Published: Jan. 10, 2024

Nuclear import of the hepatitis B virus (HBV) nucleocapsid is essential for replication that occurs in nucleus. The ~360-angstrom HBV capsid translocates to nuclear pore complex (NPC) as an intact particle, hijacking human importins a reaction stimulated by host kinases. This paper describes mechanisms recognition importins. We found importin α1 binds localization signal (NLS) at far end coat protein Cp183 carboxyl-terminal domain (CTD). NLS exposed surface through icosahedral quasi-sixfold vertex. Phosphorylation serine-155, serine-162, and serine-170 promotes CTD compaction but does not affect affinity α1. binding 30 α1/β1 augments diameter ~620 angstroms, close maximum size trafficable NPC. propose phosphorylation favors externalization prompts its surface, exposing

Language: Английский

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The Interplay between Viruses and Host DNA Sensors

Viruses, Journal Year: 2022, Volume and Issue: 14(4), P. 666 - 666

Published: March 23, 2022

DNA virus infections are often lifelong and can cause serious diseases in their hosts. Their recognition by the sensors of innate immune system represents front line host defence. Understanding molecular mechanisms immunity responses is an important prerequisite for design effective antivirotics. This review focuses on present state knowledge surrounding viral genome sensing main induced pathways responses. The studies that have been performed to date indicate herpesviruses, adenoviruses, polyomaviruses sensed various sensors. In non-immune cells, STING shown be activated cGAS, IFI16, DDX41, or DNA-PK. activation TLR9 has mainly described pDCs other cells. Importantly, herpesviruses unveiled novel participants (BRCA1, H2B, DNA-PK) IFI16 pathway. Polyomavirus revealed that, addition DNA, micronuclei released into cytosol due genotoxic stress. Papillomaviruses, HBV, HIV evade sophisticated intracellular trafficking, unique cell tropism, cellular protein actions prevent block sensing. Further research required fully understand interplay between viruses

Language: Английский

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HIV-1 capsid stability and reverse transcription are finely balanced to minimize sensing of reverse transcription products via the cGAS-STING pathway

mBio, Journal Year: 2024, Volume and Issue: 15(5)

Published: March 26, 2024

ABSTRACT A critical determinant for early post-entry events, the HIV-1 capsid (CA) protein forms conical core when it rearranges around dimeric RNA genome and associated viral proteins. Although mutations in CA have been reported to alter innate immune sensing of HIV-1, a direct link between stability nucleic acids has not established. Herein, we assessed how manipulating lattice through chemical genetic approaches affects recognition HIV-1. We found that destabilization resulted potent reverse transcription products per se does completely block transcription. Surprisingly, due combined effects enhanced defects nuclear entry, two separate mutants form hyperstable cores induced more potently than destabilizing mutations. At low concentrations allowed accumulation products, CA-targeting compounds GS-CA1 lenacapavir measurably impacted cells modestly HIV. Interestingly, activation observed with viruses containing unstable was abolished by doses lenacapavir. Innate both dependent on cGAS-STING DNA-sensing pathway Overall, our findings demonstrate are finely balanced support minimize cGAS-STING-mediated resulting DNA. IMPORTANCE In particles, proteins enzymes encased proteinaceous composed protein. altering this orthogonal impacts induction responses. Specifically, decreasing results but genomic RNA, cGAS-STING-dependent manner. The recently developed inhibitors Unexpectedly, increased levels cytosolic cDNA, also type I interferon-mediated immunity. Our suggest exposure cytosol host cells.

Language: Английский

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The Role of MicroRNAs in HIV Infection

Genes, Journal Year: 2024, Volume and Issue: 15(5), P. 574 - 574

Published: April 29, 2024

MicroRNAs (miRNAs), a class of small, non-coding RNAs, play pivotal role in regulating gene expression at the post-transcriptional level. These regulatory molecules are integral to many biological processes and have been implicated pathogenesis various diseases, including Human Immunodeficiency Virus (HIV) infection. This review aims cover current understanding multifaceted roles miRNAs assume context HIV infection pathogenesis. The discourse is structured around three primary focal points: (i) elucidation mechanisms through which regulate replication, encompassing both direct targeting viral transcripts indirect modulation host factors critical for replication; (ii) examination miRNA by HIV, mediated either proteins or activation cellular pathways consequent infection; (iii) assessment impact on immune response progression disease HIV-infected individuals. Further, this delves into potential utility as biomarkers therapeutic agents infection, underscoring challenges prospects inherent line inquiry. synthesis evidence positions significant modulators host-virus interplay, offering promising avenues enhancing diagnosis, treatment, prevention

Language: Английский

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Spatiotemporal binding of cyclophilin A and CPSF6 to capsid regulates HIV-1 nuclear entry and integration

mBio, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 27, 2025

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) capsid, which is the target of antiviral lenacapavir, protects viral genome and binds multiple host proteins to influence intracellular trafficking, nuclear import, integration. Previously, we showed that capsid binding cleavage polyadenylation specificity factor 6 (CPSF6) in cytoplasm competitively inhibited by cyclophilin A (CypA) regulates infection. Here, determined a mutant with increased CypA affinity had significantly reduced entry mislocalized However, disruption restored entry, integration, infection CPSF6-dependent manner. Furthermore, relocalization expression from cell nucleus failed restore HIV-1 Our results clarify sequential CPSF6 required for optimal integration targeting, providing insights development antiretroviral therapies, such as lenacapavir. IMPORTANCE (HIV) encodes protein forms conical shell, called surrounds its genome. The has been shown protect innate immune sensors cell, help transport toward into nucleus, keep components reverse transcription together conversion RNA DNA, DNA specific regions In this study, show HIV hijacks two bind sequentially order choreograph precise timing these replication steps. Disruption or their location leads defective Mutations exist infected individuals may reduce efficacy drugs capsid.

Language: Английский

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