Cone-shaped HIV-1 capsids are transported through intact nuclear pores

Cell, Journal Year: 2021, Volume and Issue: 184(4), P. 1032 - 1046.e18

Published: Feb. 1, 2021

Human immunodeficiency virus (HIV-1) remains a major health threat. Viral capsid uncoating and nuclear import of the viral genome are critical for productive infection. The size HIV-1 is generally believed to exceed diameter pore complex (NPC), indicating that has occur prior import. Here, we combined correlative light electron microscopy with subtomogram averaging capture structural status reverse transcription-competent complexes in infected T cells. We demonstrated NPC cellulo sufficient apparently intact, cone-shaped capsids. Subsequent import, detected disrupted empty fragments, replication occurs by breaking open, not disassembly into individual subunits. Our data directly visualize key step enhance our mechanistic understanding life cycle.

Language: Английский

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The HIV capsid mimics karyopherin engagement of FG-nucleoporins

Nature, Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 24, 2024

Abstract HIV can infect non-dividing cells because the viral capsid overcome selective barrier of nuclear pore complex and deliver genome directly into nucleus 1,2 . Remarkably, intact is more than 1,000 times larger size limit prescribed by diffusion 3 This in central channel composed intrinsically disordered nucleoporin domains enriched phenylalanine–glycine (FG) dipeptides. Through multivalent FG interactions, cellular karyopherins their bound cargoes solubilize this phase to drive nucleocytoplasmic transport 4 By performing an vitro dissection complex, we show that a pocket on surface similarly interacts with motifs from multiple nucleoporins interaction licences capsids penetrate FG-nucleoporin condensates. karyopherin mimicry model addresses key conceptual challenge for role entry offers explanation as how exogenous entity much any known cargo may be able non-destructively breach envelope.

Language: Английский

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HIV-1 capsid shape, orientation, and entropic elasticity regulate translocation into the nuclear pore complex

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(4)

Published: Jan. 19, 2024

Nuclear import and uncoating of the viral capsid are critical steps in HIV-1 life cycle that serve to transport release genomic material into nucleus. Viral core involves translocating at nuclear pore complex (NPC). Notably, central channel NPC appears often accommodate allow passage intact capsid, though mechanistic details process remain be fully understood. Here, we investigate molecular interactions operate concert between regulate translocation through channel. To this end, develop a “bottom-up” coarse-grained (CG) model human from recently released cryo-electron tomography structure then construct composite membrane-embedded CG models. We find successful cytoplasmic side is contingent on compatibility morphology dimension proper orientation approach side. The dynamics driven by maximizing contacts phenylalanine-glycine nucleoporins capsid. For docked capsids, structural analysis reveals correlated striated patterns lattice disorder likely related intrinsic elasticity. Uncondensed inside augments overall Our results suggest “elasticity” can also aid adapt stress structurally during translocation.

Language: Английский

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Pharmacologic hyperstabilisation of the HIV-1 capsid lattice induces capsid failure

eLife, Journal Year: 2024, Volume and Issue: 13

Published: Feb. 13, 2024

The HIV-1 capsid has emerged as a tractable target for antiretroviral therapy. Lenacapavir, developed by Gilead Sciences, is the first capsid-targeting drug approved medical use. Here, we investigate effect of lenacapavir on HIV stability and uncoating. We employ single particle approach that simultaneously measures content release lattice persistence. demonstrate lenacapavir's potent antiviral activity predominantly due to lethal hyperstabilisation resultant loss compartmentalisation. This study highlights disrupting metastability powerful strategy development novel antivirals.

Language: Английский

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Passage of the HIV capsid cracks the nuclear pore

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

Published: Jan. 1, 2025

Language: Английский

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Nuclear Capsid Uncoating and Reverse Transcription of HIV-1

Annual Review of Virology, Journal Year: 2022, Volume and Issue: 9(1), P. 261 - 284

Published: June 15, 2022

After cell entry, human immunodeficiency virus type 1 (HIV-1) replication involves reverse transcription of the RNA genome, nuclear import subviral complex without envelope breakdown, and integration viral complementary DNA into host genome. Here, we discuss recent evidence indicating that completion genome uncoating occur in nucleus rather than cytoplasm, as previously thought, suggest a testable model for uncoating. Multiple studies indicated cone-shaped capsid, which encases proteins, not only serves reaction container shield from innate immune sensors but also may constitute elusive HIV-1 factor. Rupture capsid be triggered by transcription, yet-unknown factors, or physical damage, it appears to close temporal spatial association with process.

Language: Английский

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Evasion of cGAS and TRIM5 defines pandemic HIV

Nature Microbiology, Journal Year: 2022, Volume and Issue: 7(11), P. 1762 - 1776

Published: Oct. 26, 2022

Abstract Of the 13 known independent zoonoses of simian immunodeficiency viruses to humans, only one, leading human virus (HIV) type 1(M) has become pandemic, causing over 80 million infections. To understand specific features associated with pandemic human-to-human HIV spread, we compared replication HIV-1(M) non-pandemic HIV-(O) and HIV-2 strains in myeloid cell models. We found that lineages replicate less well than owing activation cGAS TRIM5-mediated antiviral responses. applied phylogenetic X-ray crystallography structural analyses identify differences between capsids. genetic reversal two amino acid adaptations enables TRIM5, innate immune propose a model which parental lineage evolved capsid prevents TRIM5 triggering, thereby allowing silent cells. hypothesize this adaptation promotes spread through avoidance response activation.

Language: Английский

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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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The HIV-1 capsid core is an opportunistic nuclear import receptor

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: June 24, 2023

Abstract The movement of viruses and other large macromolecular cargo through nuclear pore complexes (NPCs) is poorly understood. human immunodeficiency virus type 1 (HIV-1) provides an attractive model to interrogate this process. HIV-1 capsid (CA), the chief structural component viral core, a critical determinant in transport virus. interactions with NPCs are dependent on CA, which makes direct contact nucleoporins (Nups). Here we identify Nup35, Nup153, POM121 coordinately support entry. For Nup35 POM121, dependence was cyclophilin A (CypA) interaction CA. Mutation CA or removal soluble host factors changed NPC. make via regions containing phenylalanine glycine motifs (FG-motifs). Collectively, these findings provide additional evidence that core functions as receptor (NTR) exploits modulate NPC requirements during invasion.

Language: Английский

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Function and regulation of cGAS-STING signaling in infectious diseases

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: Feb. 6, 2023

The efficacious detection of pathogens and prompt induction innate immune signaling serve as a crucial component defense against infectious pathogens. Over the past decade, DNA-sensing receptor cyclic GMP-AMP synthase (cGAS) its downstream adaptor stimulator interferon genes (STING) have emerged key mediators type I (IFN) nuclear factor-κB (NF-κB) responses in health infection diseases. Moreover, both cGAS-STING pathway developed delicate strategies to resist each other for their survival. mechanistic functional comprehension interplay between is opening way development application pharmacological agonists antagonists treatment Here, we briefly review current knowledge DNA sensing through pathway, emphatically highlight potent undertaking host pathogenic organisms.

Language: Английский

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