Interplay between the cyclophilin homology domain of RANBP2 and MX2 regulates HIV-1 capsid dependencies on nucleoporins

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

Published: Jan. 24, 2025

ABSTRACT Interlinked interactions between the viral capsid (CA), nucleoporins (Nups), and antiviral protein myxovirus resistance 2 (MX2/MXB) influence human immunodeficiency virus 1 (HIV-1) nuclear entry outcome of infection. Although RANBP2/NUP358 has been repeatedly identified as a critical player in HIV-1 import MX2 activity, mechanism by which RANBP2 facilitates infection is not well understood. To explore MX2, CA, RANBP2, we utilized CRISPR-Cas9 to generate cell lines expressing from its endogenous locus but lacking C-terminal cyclophilin (Cyp) homology domain found that both HIV-2 infections were reduced significantly ΔCyp cells. Importantly, although still localized pore complex cells, activity against was decreased. By generating cells specific point mutations RANBP2-Cyp domain, determined effect on anti-HIV-1 due direct CA. We further CypA have similar effects integration targeting. Finally, Nup requirements for HIV altered domain. These findings demonstrate affects sensitivity altering CA-specific with cellular factors affect IMPORTANCE Human into nucleus an essential step replication involves (CA) multiple proteins, including (Nups) such RANBP2. Nups also mediate function (MX2); however, determining precise role proved challenging nature (NPC) significant pleiotropic elicited depletion. used gene editing assess activity. find this infection, nucleoporin requirements, sensitivity, targeting manner, providing detailed insights how contributes

Language: Английский

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Lenacapavir disrupts HIV-1 core integrity while stabilizing the capsid lattice

Proceedings of the National Academy of Sciences, Journal Year: 2025, Volume and Issue: 122(14)

Published: April 1, 2025

Lenacapavir (GS-6207; LEN) is a potent HIV-1 capsid inhibitor approved for treating multidrug-resistant infection. LEN binds to hydrophobic pocket between neighboring (CA) proteins in hexamers and stabilizes the lattice, but its effect on capsids not fully understood. Here, we labeled with green fluorescent protein fused CA (GFP-CA) or fluid-phase GFP content marker (cmGFP) assess LEN’s impact capsids. cores GFP-CA, cmGFP, could be immunostained an anti-GFP antibody were less sensitive capsid-binding host restriction factor MX2, demonstrating that GFP-CA incorporated into lattice stability, whereas cmGFP indicator of core integrity. treatment isolated resulted dose-dependent loss signal while preserving signal, indicating disrupts integrity lattice. In contrast, PF-3450074 (PF74) induced Electron microscopy LEN- PF74-treated viral revealed frequent breakage at narrow end other morphological changes. Our results suggest does prevent nuclear envelope docking inhibits import without PF74 blocks by inhibiting cores, highlighting their different mechanisms inhibition.

Language: Английский

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Cyclophilin A Regulates Tripartite Motif 5 Alpha Restriction of HIV-1

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(2), P. 495 - 495

Published: Jan. 9, 2025

The peptidyl-prolyl isomerase A (PPIA), also known as cyclophilin (CYPA), is involved in multiple steps of the HIV-1 replication cycle. CYPA regulates restriction many host factors by interacting with CYPA-binding loop on capsid (CA) surface. TRIM5 (tripartite motif protein 5) primates a key species-specific factor defining pandemic. incomplete adaptation to humans due different utilization pandemic and non-pandemic HIV-1. enzymatic activity viral core likely an important reason for regulating activity. Thus, its interaction may serve new targets future anti-AIDS therapeutic agents. This article will describe species-specificity TRIM5, understand role retroviral infection, discuss research issues.

Language: Английский

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Hurdles to healing: Overcoming cellular barriers for viral and nonviral gene therapy

International Journal of Pharmaceutics, Journal Year: 2025, Volume and Issue: unknown, P. 125470 - 125470

Published: March 1, 2025

Language: Английский

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dNTP depletion and beyond: the multifaceted nature of SAMHD1-mediated viral restriction

Journal of Virology, Journal Year: 2025, Volume and Issue: unknown

Published: April 25, 2025

ABSTRACT SAMHD1 is a dNTPase of mammalian cells. In 2011, was found to be host restriction factor against retroviruses through dNTP reduction. Recent research provides evidence that the antiviral mechanisms cannot explained solely by its activity. Instead, versatility SAMHD1-mediated various viruses suggests extend beyond depletion. This explains multifaceted and broad functions play significant role in innate immunity.

Language: Английский

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Clicking viruses—with chemistry toward mechanisms in infection

Journal of Virology, Journal Year: 2025, Volume and Issue: unknown

Published: May 14, 2025

ABSTRACT Viruses subvert cells and evade host defense. They emerge unpredictably threaten humans livestock through their genetic phenotypic diversity. Despite more than 100 years since the discovery of viruses, molecular underpinnings virus infections are incompletely understood. The introduction new methodologies into field, such as that click chemistry some 10 ago, keeps uncovering facets viruses. Click uses bio-orthogonal reactions on chemical probes couples nucleic acids, proteins, lipids with tractable labels, fluorophores for single-cell single-molecule imaging, or biotin biochemical profiling infections. Its applications in single often achieve resolution provide important insights widely known phenomenon cell-to-cell infection variability. This review describes advances to unravel mechanisms a select set enveloped nonenveloped DNA RNA including adenovirus, herpesvirus, human immunodeficiency virus. It highlights recent breakthroughs viral DNA, RNA, protein, well host-derived lipid functions both live chemically fixed cells. discusses specific processes entry, uncoating, transcription, replication, packaging, assembly provides perspective explore cell biology, variability, genome organization particle.

Language: Английский

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Kaposi’s sarcoma-associated herpesvirus induces mitochondrial fission to evade host immune responses and promote viral production

Nature Microbiology, Journal Year: 2025, Volume and Issue: unknown

Published: May 22, 2025

Language: Английский

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Mimicry games: NPC-like MX2 condensates trap viruses

Cell Host & Microbe, Journal Year: 2024, Volume and Issue: 32(10), P. 1645 - 1648

Published: Oct. 1, 2024

Language: Английский

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Nuclear pore decoys fool viruses

Science Signaling, Journal Year: 2024, Volume and Issue: 17(859)

Published: Oct. 22, 2024

Cytoplasmic condensates that mimic nuclear pore complexes entice viruses away from the nucleus.

Language: Английский

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