Interactions of HIV-1 Capsid with Host Factors and Their Implications for Developing Novel Therapeutics

Viruses, Journal Year: 2021, Volume and Issue: 13(3), P. 417 - 417

Published: March 5, 2021

The Human Immunodeficiency Virus type 1 (HIV-1) virion contains a conical shell, termed capsid, encasing the viral RNA genome. After cellular entry of virion, capsid is released and ensures protection delivery HIV-1 genome to host nucleus for integration. relies on many virus-host factor interactions which are regulated spatiotemporally throughout course infection. In this paper, we will review current understanding highly dynamic capsid-host interplay during early stages replication, namely intracellular trafficking after fusion, nuclear import, uncoating, integration into chromatin. Conventional anti-retroviral therapies primarily target enzymes. Insights structure have resulted in first-in-class, long-acting capsid-targeting inhibitor, GS-6207 (Lenacapavir). This inhibitor binds at interface between protein subunits, site known bind factors, interferes with HIV particle assembly, ordered assembly. Our highlight structure, factors that interact high-throughput screening techniques, specifically genomic proteomic approaches, been can be used identify capsid. Better structural mechanistic insights significantly inform pathogenesis development capsid-centric antiretroviral therapeutics.

Language: Английский

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Advances in HIV-1 Assembly

Viruses, Journal Year: 2022, Volume and Issue: 14(3), P. 478 - 478

Published: Feb. 26, 2022

The assembly of HIV-1 particles is a concerted and dynamic process that takes place on the plasma membrane infected cells. An abundance recent discoveries has advanced our understanding complex sequence events leading to particle assembly, budding, release. Structural studies have illuminated key features maturation, including dramatic structural transition occurs between immature Gag lattice formation mature viral capsid core. critical role inositol hexakisphosphate (IP6) in both been elucidated. basis for selective packaging genomic RNA into virions revealed. This review will provide an overview process, with focus advances field, point out areas where questions remain can benefit from future investigation.

Language: Английский

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A Review on FDA Approved Anti-HIV-1 Drugs, Anti-Gag Compounds and Potential Strategies for HIV-1 Eradication

Published: Jan. 18, 2024

Acquired immunodeficiency syndrome (AIDS) is an enormous global health threat stemming from human virus (HIV-1) infection. Up to now, the tremendous advances in combination antiretroviral therapy (cART) have shifted HIV-1 infection a fatal illness into manageable chronic disorder. However, presence of latent reservoirs, multifaceted nature HIV-1, drug resistance, severe off-target effects, poor adherence, and high cost restrict efficacy current cART targeting distinct stages life cycle. Therefore, there unmet need for discovery new therapeutics that not only bypass limitations but also protect body at same time. The main goal complete eradication purging latently infected cells patients’ bodies. A potential strategy called “lock-in apoptosis” budding phase cycle leading susceptibility apoptosis elimination reservoirs ultimately eradication. work intends present advantages disadvantages United States Food Drug Administration (FDA) approved anti-HIV-1 drugs as well plausible strategies design development more compounds with better potency, favorable pharmacokinetic profiles, improved safety issues.

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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Role of TLRs in HIV-1 Infection and Potential of TLR Agonists in HIV-1 Vaccine Development and Treatment Strategies

Pathogens, Journal Year: 2023, Volume and Issue: 12(1), P. 92 - 92

Published: Jan. 5, 2023

Toll-like receptors (TLRs), as a family of pattern recognition receptors, play an important role in the HIV-1 molecular structures by various cells innate immune system, but also provide functional association with subsequent mechanisms adaptive immunity. TLR7 and TLR8 particularly response to RNA viruses due their ability recognise GU-rich single-stranded molecules subsequently activate intracellular signalling pathways resulting expression genes coding for biological modifiers (interferons, proinflammatory cytokines, chemokines). The aim this review is summarise most recent knowledge on TLRs TLR gene polymorphisms biology clinical aspects HIV infections. In addition, agonists latency reversing agents research treat infections immunomodulators vaccine will be discussed.

Language: Английский

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HIV-1 capsid and viral DNA integration

mBio, Journal Year: 2023, Volume and Issue: 15(1)

Published: Dec. 12, 2023

ABSTRACT The human immunodeficiency virus type 1 (HIV-1) genome encodes 15 proteins that perform structural, enzymatic, regulatory, and accessory functions. capsid protein (CA) is the primary structural of HIV-1 plays multiple functions during infection. Early studies predicted CA mainly protected delivered viral to target cell. However, it now well established a critical role after cellular entry steps During early stages, promotes reverse transcription RNA into DNA copy nuclear import/entry step Emerging evidence also supports functional in post-nuclear infection, such as integration. late stages coordinates hexameric lattice formation for assembly immature virion. regulates theformation mature encases associated factors infectious progeny Because these indispensable roles, has emerged new validated antiviral drug development. Accordingly, first CA-targeting drug, lenacapavir (GS-6207), was recently approved treat certain HIV-1-infected individuals whose load cannot be controlled by other drugs. Still, superior inhibitors are needed qualify part front-line therapy regimens all infected individuals. development requires clear understanding CA’s In this review, we will describe with particular emphasis on steps. IMPORTANCE (CA)—independently or recruiting host factors—mediates several key replication cytoplasm nucleus Research recent years have multifunctional genetically fragile proteins. high priority therapeutic target, treating multi-drug resistant next generation depends better known probing novel replication. timely present an updated overview current state our replication—with special newfound highlight pressing knowledge gaps, discuss directions future research.

Language: Английский

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The Discovery of GSK3640254, a Next-Generation Inhibitor of HIV-1 Maturation

Journal of Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 65(18), P. 11927 - 11948

Published: Aug. 31, 2022

GSK3640254 is an HIV-1 maturation inhibitor (MI) that exhibits significantly improved antiviral activity toward a range of clinically relevant polymorphic variants with reduced sensitivity the second-generation MI GSK3532795 (BMS-955176). The key structural difference between and its predecessor replacement para-substituted benzoic acid moiety attached at C-3 position triterpenoid core cyclohex-3-ene-1-carboxylic substituted CH2F carbon atom α- to pharmacophoric carboxylic acid. This element provided new vector which explore structure-activity relationships (SARs) led compounds coverage while preserving pharmacokinetic (PK) properties. approach design GSK3640254, development synthetic route preclinical profile are discussed. currently in phase IIb clinical trials after demonstrating dose-related reduction viral load over 7-10 days dosing HIV-1-infected subjects.

Language: Английский

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Inhibition of neutral sphingomyelinase 2 impairs HIV-1 envelope formation and substantially delays or eliminates viral rebound

Proceedings of the National Academy of Sciences, Journal Year: 2023, Volume and Issue: 120(28)

Published: July 5, 2023

Although HIV-1 Gag is known to drive viral assembly and budding, the precise mechanisms by which lipid composition of plasma membrane remodeled during are incompletely understood. Here, we provide evidence that sphingomyelin hydrolase neutral sphingomyelinase 2 (nSMase2) interacts with through hydrolysis creates ceramide necessary for proper formation envelope maturation. Inhibition or depletion nSMase2 resulted in production noninfectious virions incomplete lattices lacking condensed conical cores. HIV-1-infected humanized mouse models a potent selective inhibitor termed PDDC [phenyl(R)-(1-(3-(3,4-dimethoxyphenyl)-2, 6-dimethylimidazo[1,2-b]pyridazin-8-yl) pyrrolidin-3-yl)-carbamate] produced linear reduction levels plasma. If undetectable were achieved treatment, rebound did not occur up 4 wk when was discontinued. In vivo tissue culture results suggest selectively kills cells actively replicating HIV-1. Collectively, this work demonstrates critical regulator replication suggests could be an important therapeutic target potential kill cells.

Language: Английский

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The Effect of Inositol Hexakisphosphate on HIV-1 Particle Production and Infectivity can be Modulated by Mutations that Affect the Stability of the Immature Gag Lattice

Journal of Molecular Biology, Journal Year: 2023, Volume and Issue: 435(11), P. 168037 - 168037

Published: June 1, 2023

Language: Английский

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Neutral sphingomyelinase 2 is required for HIV-1 maturation

Proceedings of the National Academy of Sciences, Journal Year: 2023, Volume and Issue: 120(28)

Published: July 5, 2023

HIV-1 assembly occurs at the inner leaflet of plasma membrane (PM) in highly ordered microdomains. The size and stability microdomains is regulated by activity sphingomyelin hydrolase neutral sphingomyelinase 2 (nSMase2) that localized primarily to PM. In this study, we demonstrate pharmacological inhibition or depletion nSMase2 HIV-1-producer cells results a block processing major viral structural polyprotein Gag production morphologically aberrant, immature particles with severely impaired infectivity. We find disruption also inhibits maturation infectivity other primate lentiviruses HIV-2 simian immunodeficiency virus, has modest no effect on nonprimate equine infectious anemia virus feline gammaretrovirus murine leukemia virus. These studies key role for particle morphogenesis maturation.

Language: Английский

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