Structure, Function, and Interactions of the HIV-1 Capsid Protein

Life, Journal Year: 2021, Volume and Issue: 11(2), P. 100 - 100

Published: Jan. 29, 2021

The capsid (CA) protein of the human immunodeficiency virus type 1 (HIV-1) is an essential structural component a virion and facilitates many crucial life cycle steps through interactions with host cell factors. Capsid shields reverse transcription complex from restriction factors while it enables trafficking to nucleus by hijacking various adaptor proteins, such as FEZ1 BICD2. In addition, import localization viral in interaction NUP153, NUP358, TNPO3, CPSF-6. later stages HIV-1 cycle, CA plays role maturation step constituent Gag polyprotein. final phase maturation, cleaved, released, allowing for assembly into fullerene cone, known core. cone consists ~250 hexamers 12 pentamers encloses genome other proteins next round infection. As research continues elucidate importance becomes more apparent, displays potential therapeutic target development inhibitors.

Language: Английский

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Identification of DAXX as a restriction factor of SARS-CoV-2 through a CRISPR/Cas9 screen

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: May 4, 2022

Interferon restricts SARS-CoV-2 replication in cell culture, but only a handful of Stimulated Genes with antiviral activity against have been identified. Here, we describe functional CRISPR/Cas9 screen aiming at identifying restriction factors. We identify DAXX, scaffold protein residing PML nuclear bodies known to limit the DNA viruses and retroviruses, as potent inhibitor SARS-CoV human cells. Basal expression DAXX is sufficient SARS-CoV-2, over-expression further infection. an early, post-entry step life cycle. DAXX-mediated independent SUMOylation pathway dependent on its D/E domain, also necessary for protein-folding activity. infection triggers re-localization cytoplasmic sites promotes degradation. Mechanistically, this process mediated by viral papain-like protease (PLpro) proteasome. Together, these results demonstrate that which turn has evolved mechanism counteract action.

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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HIV Capsid and Integration Targeting

Viruses, Journal Year: 2021, Volume and Issue: 13(1), P. 125 - 125

Published: Jan. 18, 2021

Integration of retroviral reverse transcripts into the chromosomes cells that they infect is required for efficient viral gene expression and inheritance genomes to daughter cells. Before integration can occur, transcription complexes (RTCs) must access nuclear environment where reside. Retroviral non-random, with different types virus-host interactions impacting in host chromatin takes place. Lentiviruses such as HIV efficiently interphase because their RTCs have evolved usurp cellular import transport mechanisms, research over past decade has revealed specific between capsid protein nucleoporin (Nup) proteins Nup358 Nup153. The interaction cleavage polyadenylation specificity factor 6 (CPSF6), which a component complex, helps dictate well post-nuclear RTC invasion. In absence capsid-CPSF6 interaction, are precluded from reaching speckles gene-rich regions known speckle-associated domains, instead mis-target lamina-associated domains out at periphery. Highlighting this area research, small molecules inhibit capsid-host important site targeting highly potent antiviral compounds.

Language: Английский

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The antiviral state of the cell: lessons from SARS-CoV-2

Current Opinion in Immunology, Journal Year: 2024, Volume and Issue: 87, P. 102426 - 102426

Published: April 1, 2024

Language: Английский

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HIV-1 capsid variability: viral exploitation and evasion of capsid-binding molecules

Retrovirology, Journal Year: 2021, Volume and Issue: 18(1)

Published: Oct. 26, 2021

Abstract The HIV-1 capsid, a conical shell encasing viral nucleoprotein complexes, is involved in multiple post-entry processes during replication. Many host factors can directly bind to the capsid protein (CA) and either promote or prevent infection. currently being explored as novel target for therapeutic interventions. In past few decades, significant progress has been made our understanding of capsid–host interactions mechanisms action capsid-targeting antivirals. At same time, large number different capsids, which derive from many mutants, naturally occurring variants, diverse lentiviruses, have characterized their with capsid-binding molecules great detail utilizing various experimental techniques. This review provides an overview how sequence variation CA influences phenotypic properties HIV-1. We will focus on differences that alter give brief account drug resistant mutations mutational effects phenotypes. Increased knowledge sequence-function relationship helps us deepen adaptive potential capsid.

Language: Английский

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Nuclear Import of HIV-1

Viruses, Journal Year: 2021, Volume and Issue: 13(11), P. 2242 - 2242

Published: Nov. 8, 2021

The delivery of the HIV-1 genome into nucleus is an indispensable step in retroviral infection non-dividing cells, but mechanism nuclear import has been a longstanding debate due to controversial experimental evidence. It was commonly believed that capsid would need disassemble (uncoat) cytosol before because larger than central channel pore complexes (NPCs); however, increasing evidence demonstrates intact, or nearly passes through NPC enter nucleus. With protection capsid, core completes reverse transcription and translocated integration site. Uncoating occurs while, after, viral released near These independent discoveries reveal compelling new paradigm this important life cycle. In review, we summarize recent studies related import, highlighting spatial-temporal relationship between entry virus core, transcription, uncoating.

Language: Английский

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Regulation of viral replication by host restriction factors

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: Jan. 23, 2025

Viral infectious diseases, caused by numerous viruses including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), influenza A virus (IAV), enterovirus (EV), human immunodeficiency (HIV), hepatitis B (HBV), and papillomavirus (HPV), pose a continuous threat to global health. As obligate parasites, rely on host cells replicate, have developed defense mechanisms counteract viral infection. Host restriction factors (HRFs) are critical components of the early antiviral response. These cellular proteins inhibit replication spread impeding essential steps in life cycle, such as entry, genome transcription replication, protein translation, particle assembly, release. This review summarizes current understanding how with primary focus their diverse against range viruses, SARS-CoV-2, virus, enteroviruses, papillomavirus. In addition, we highlight crucial role these shaping host-virus interactions discuss potential targets for drug development.

Language: Английский

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HIV-1 Nucleocapsid Protein Binds Double-Stranded DNA in Multiple Modes to Regulate Compaction and Capsid Uncoating

Viruses, Journal Year: 2022, Volume and Issue: 14(2), P. 235 - 235

Published: Jan. 25, 2022

The HIV-1 nucleocapsid protein (NC) is a multi-functional necessary for viral replication. Recent studies have demonstrated reverse transcription occurs inside the fully intact capsid and that timing of uncoating are correlated. How nearly 10 kbp DNA genome stably contained within narrow with diameter similar to persistence length double-stranded (ds) DNA, role NC in this process, not well understood. In study, we use optical tweezers, fluorescence imaging, atomic force microscopy observe binding single long substrate multiple modes. We find binds saturates non-specific mode triggers uniform self-attraction, condensing into tight globule at constant up pN. When removed from solution, dissipates over time, but specifically-bound maintains long-range looping less compact highly stable. Both modes additionally observed using AFM imaging. These results suggest conformation compatible transcription, regulating genomic pressure on preventing premature uncoating.

Language: Английский

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Interferon-stimulated genes and their antiviral activity against SARS-CoV-2

mBio, Journal Year: 2024, Volume and Issue: 15(9)

Published: Aug. 22, 2024

ABSTRACT The coronavirus disease 2019 (COVID-19) pandemic remains an international health problem caused by the recent emergence of severe acute respiratory syndrome 2 (SARS-CoV-2). As May 2024, SARS-CoV-2 has more than 775 million cases and over 7 deaths globally. Despite current vaccination programs, infections are still rapidly increasing, mainly due to appearance spread new variants, variations in immunization rates, limitations vaccines preventing transmission. This underscores need for pan-variant antivirals treatments. interferon (IFN) system is a critical element innate immune response serves as frontline defense against viruses. It induces generalized antiviral state transiently upregulating hundreds IFN-stimulated genes (ISGs). To gain deeper comprehension SARS-CoV-2, its connection COVID-19 pathogenesis, potential therapeutic implications, this review provides detailed overview fundamental aspects diverse ISGs identified their properties SARS-CoV-2. emphasizes importance these proteins controlling viral replication spread. Furthermore, we explore methodological approaches identification conduct comparative analysis with other Deciphering roles interactions pathogens can help identify novel targets therapies enhance our preparedness confront future threats.

Language: Английский

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