Exploring HIV-1 Maturation: A New Frontier in Antiviral Development DOI Creative Commons
Aidan McGraw,

Grace Hillmer,

Stefania M. Medehincu

et al.

Viruses, Journal Year: 2024, Volume and Issue: 16(9), P. 1423 - 1423

Published: Sept. 6, 2024

HIV-1 virion maturation is an essential step in the viral replication cycle to produce infectious virus particles. Gag and Gag-Pol polyproteins are assembled at plasma membrane of virus-producer cells bud from it extracellular compartment. The newly released progeny virions initially immature noninfectious. However, once polyprotein cleaved by protease virions, mature capsid proteins assemble form fullerene core. This core, harboring two copies genomic RNA, transforms morphology into morphological transformation referred as maturation. Virion influences distribution Env glycoprotein on surface induces conformational changes necessary for subsequent interaction with CD4 receptor. Several host factors, including like cyclophilin A, metabolites such IP6, lipid rafts containing sphingomyelins, have been demonstrated influence review article delves processes recruitment, emphasis role cell factors environmental conditions. Additionally, we discuss microscopic technologies assessing development current antivirals specifically targeting this critical replication, offering long-acting therapeutic options.

Language: Английский

HIV-1 is dependent on its immature lattice to recruit IP6 for mature capsid assembly DOI

Nadine Renner,

Alex B. Kleinpeter, Donna L. Mallery

et al.

Nature Structural & Molecular Biology, Journal Year: 2023, Volume and Issue: 30(3), P. 370 - 382

Published: Jan. 9, 2023

Language: Английский

Citations

44
Pharmacologic hyperstabilisation of the HIV-1 capsid lattice induces capsid failure DOI Creative Commons

K. Faysal,

James Walsh,

Nadine Renner

et al.

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

Citations

19
Critical mechanistic features of HIV-1 viral capsid assembly DOI Creative Commons

Manish Gupta,

Alexander J. Pak, Gregory A. Voth

et al.

Science Advances, Journal Year: 2023, Volume and Issue: 9(1)

Published: Jan. 6, 2023

The maturation of HIV-1 capsid protein (CA) into a cone-shaped lattice is critical for viral infectivity. CA can self-assemble range morphologies made ~175 to 250 hexamers and 12 pentamers. cellular polyanion inositol hexakisphosphate (IP6) has recently been demonstrated facilitate conical formation by coordinating ring arginine residues within the central cavity However, kinetic interplay events during IP6 coassembly unclear. In this work, we use coarse-grained molecular dynamics simulations elucidate mechanism formation, including role played IP6. We show that IP6, in small quantities at first, promotes curvature generation trapping pentameric defects growing shifts assembly behavior toward kinetically favored outcomes. Our analysis also suggests stabilize metastable intermediates induce structural pleomorphism mature capsids.

Language: Английский

Citations

37
The capsid lattice engages a bipartite NUP153 motif to mediate nuclear entry of HIV-1 cores DOI Creative Commons
Qi Shen, Sushila Kumari, Chaoyi Xu

et al.

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

Citations

34
Structural insights into HIV-1 polyanion-dependent capsid lattice formation revealed by single particle cryo-EM DOI Creative Commons
Carolyn M. Highland, Aaron Tan, Clifton Ricana

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2023, Volume and Issue: 120(18)

Published: April 24, 2023

The HIV-1 capsid houses the viral genome and interacts extensively with host cell proteins throughout life cycle. It is composed of protein (CA), which assembles into a conical fullerene lattice roughly 200 CA hexamers 12 pentamers. Previous structural analyses individual pentamers have provided valuable insight structure function, but detailed information about these assemblies in broader context lacking. In this study, we combined cryoelectron tomography single particle analysis (SPA) microscopy to determine structures continuous regions containing both We also developed method liposome scaffold-based vitro assembly ("lattice templating") that enabled us directly study under wider range conditions than has previously been possible. Using approach, identified critical role for inositol hexakisphosphate pentamer formation determined bound capsid-targeting antiretroviral drug GS-6207 (lenacapavir). Our work reveals key details mature establishes combination templating SPA as robust strategy studying retroviral interactions antiviral compounds.

Language: Английский

Citations

32
Capsid–host interactions for HIV-1 ingress DOI
Sooin Jang, Alan Engelman

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

Citations

25
Co-opting templated aggregation to degrade pathogenic tau assemblies and improve motor function DOI Creative Commons
Lauren V. C. Miller, Guido Papa, Marina Vaysburd

et al.

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

Published: Sept. 1, 2024

Language: Английский

Citations

14
HIV-1 Capsid Uncoating Is a Multistep Process That Proceeds through Defect Formation Followed by Disassembly of the Capsid Lattice DOI Creative Commons

Levi B. Gifford,

Gregory B. Melikyan

ACS Nano, Journal Year: 2024, Volume and Issue: 18(4), P. 2928 - 2947

Published: Jan. 19, 2024

The HIV-1 core consists of a cone-shaped capsid shell made protein (CA) hexamers and pentamers encapsulating the viral genome. disassembly, referred to as uncoating, is important for productive infection; however, location, timing, regulation uncoating remain controversial. Here, we employ amber codon suppression directly label CA. In addition, fluid phase fluorescent probe incorporated into detect small defects in lattice. This double-labeling strategy enables visualization single cores vitro living cells, which found always proceed through at least two distinct steps─the formation defect lattice that initiates gradual loss CA below detectable level. Importantly, intact containing markers enter uncoat nucleus, evidenced by sequential both markers, prior establishing infection. two-step process observed different including macrophage line. Notably, lag between release marker terminal appears be independent cell type or reverse transcription much longer (>5-fold) nuclear capsids compared cell-free cytosol, suggesting stabilized capsid-binding factors. Our results imply nucleus initiated localized global

Language: Английский

Citations

11
Structure of native HIV-1 cores and their interactions with IP6 and CypA DOI Creative Commons
Tao Ni, Yanan Zhu, Zhengyi Yang

et al.

Science Advances, Journal Year: 2021, Volume and Issue: 7(47)

Published: Nov. 19, 2021

High-resolution cryoET structures of native HIV-1 capsid in complex with IP6 and CypA are enabled by viral membrane perforation.

Language: Английский

Citations

48
IP6‐stabilised HIV capsids evade cGAS/STING‐mediated host immune sensing DOI Creative Commons
Guido Papa, Anna Albecka, Donna L. Mallery

et al.

EMBO Reports, Journal Year: 2023, Volume and Issue: 24(5)

Published: March 27, 2023

Abstract HIV‐1 uses inositol hexakisphosphate (IP6) to build a metastable capsid capable of delivering its genome into the host nucleus. Here, we show that viruses are unable package IP6 lack protection and detected by innate immunity, resulting in activation an antiviral state inhibits infection. Disrupting enrichment results defective capsids trigger cytokine chemokine responses during infection both primary macrophages T‐cell lines. Restoring with single mutation rescues ability infect cells without being detected. Using combination mutants CRISPR‐derived knockout cell lines for RNA DNA sensors, immune sensing is dependent upon cGAS–STING axis independent detection. Sensing requires synthesis viral prevented reverse transcriptase inhibitors or active‐site mutation. These demonstrate required can successfully transit avoid sensing.

Language: Английский

Citations

21