Antiviral factors and their counteraction by HIV-1: many uncovered and more to be discovered

Journal of Molecular Cell Biology, Journal Year: 2024, Volume and Issue: 16(2)

Published: Feb. 1, 2024

Extensive studies on HIV-1 have led to the discovery of a variety structurally and functionally diverse innate defense factors that target various steps retroviral replication cycle. Some them, such as APOBEC3, tetherin, SERINC5, are well established. Their importance is evident from fact uses its accessory proteins Vif, Vpu, Nef counteract them. However, list antiviral constantly increasing, accumulating evidence suggests mechanisms, which restrict and/or counteracted by viral proteins, remain be discovered. These relevant diseases other than HIV/AIDS, since they commonly active against pathogens. In this review, we provide an overview recently reported antiretroviral countermeasures, present suggesting more mechanisms discovered, discuss why challenging but rewarding task.

Language: Английский

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Viruses and the Brain—A Relationship Prone to Trouble

Viruses, Journal Year: 2025, Volume and Issue: 17(2), P. 203 - 203

Published: Jan. 31, 2025

Neurological disorders, some of which are associated with viral infections, growing due to the aging and expanding population. Despite strong defenses central nervous system, viruses have evolved ways breach them, often result in dire consequences. In this review, we recount various by different can enter CNS, describe consequences such invasions. Consequences may manifest as acute disease, encephalitis, meningitis, or long-term effects, neuromuscular dysfunction, occurs poliomyelitis. We discuss evidence for involvement causation well-known chronic neurodegenerative diseases, Alzheimer's Parkinson's amyotrophic lateral sclerosis, multiple well vascular dementia elderly. also approaches currently available control a few neural infections. These include antivirals that effective against human immunodeficiency virus herpes simplex virus, vaccines valuable controlling rabies poliomyelitis flavivirus There is an urgent need better understand, at molecular level, how contribute and, especially, neurological diseases develop more precise therapies.

Language: Английский

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Centrosome amplification and aneuploidy driven by the HIV-1-induced Vpr•VprBP•Plk4 complex in CD4+ T cells

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: March 5, 2024

Abstract HIV-1 infection elevates the risk of developing various cancers, including T-cell lymphoma. Whether HIV-1-encoded proteins directly contribute to oncogenesis remains unknown. We observe that approximately 1–5% CD4 + T cells from blood people living with exhibit over-duplicated centrioles, suggesting centrosome amplification underlies development HIV-1-associated cancers by driving aneuploidy. Through affinity purification, biochemical, and cellular analyses, we discover Vpr, an accessory protein HIV-1, hijacks centriole duplication machinery induces Mechanistically, Vpr forms a cooperative ternary complex E3 ligase subunit, VprBP, polo-like kinase 4 (Plk4). Unexpectedly, however, enhances Plk4’s functionality promoting its relocalization procentriole assembly amplification. Loss either Vpr’s C-terminal 17 residues or VprBP acidic region, two elements required for binding Plk4 cryptic polo-box, abrogates capacity induce these events. Furthermore, WT, but not mutant, multiple centrosomes aneuploidy in human primary cells. propose Vpr•VprBP•Plk4 serves as molecular link connects inhibiting motif may reduce occurrence cancers.

Language: Английский

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HIV-1 Vpr Functions in Primary CD4+ T Cells

Viruses, Journal Year: 2024, Volume and Issue: 16(3), P. 420 - 420

Published: March 9, 2024

HIV-1 encodes four accesory proteins in addition to its structural and regulatory genes. Uniquely amongst them, Vpr is abundantly present within virions, meaning it poised exert various biological effects on the host cell upon delivery. In this way, contributes towards establishment of a successful infection, as evidenced by extent which depends factor achieve full pathogenicity vivo. Although HIV infects types organism, CD4+ T cells are preferentially targeted since they highly permissive productive concomitantly bringing about hallmark immune dysfunction that accompanies spread. The last several decades have seen unprecedented progress unraveling activities possesses at molecular scale, increasingly underscoring importance viral component. Nevertheless, remains controversial whether some these advances bear vivo relevance, commonly employed cellular models significantly differ from primary lymphocytes. One prominent example “established” ability induce G2 cycle arrest, with enigmatic physiological relevance infected objective review discoveries their context illustrate mechanisms whereby supports infection cells, whilst identifying findings require validation physiologically relevant models.

Language: Английский

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Drug Repurposing Approaches to Combating Viral Infections

Journal of Clinical Medicine, Journal Year: 2020, Volume and Issue: 9(11), P. 3777 - 3777

Published: Nov. 23, 2020

Development of novel antiviral molecules from the beginning costs an average $350 million to $2 billion per drug, and journey laboratory clinic takes about 10–15 years. Utilization drug repurposing approaches has generated substantial interest in order overcome these drawbacks. A drastic reduction failure rate, which otherwise is ~92%, achieved with approach. The recent exploration approach combat COVID-19 pandemic further validated fact that it more beneficial reinvestigate in-practice drugs for a new application instead designing drugs. first successful example zidovudine (AZT), was developed as anti-cancer agent 1960s later approved by US FDA anti-HIV therapeutic late 1980s after fast track clinical trials. Since time, been successfully utilized develop effective strategies against plethora diseases. Hence, extensive will not only help fight current pandemics efficiently but also predict prepare newly emerging viral infections. In this review, we discuss detail its advancements related infections such Human Immunodeficiency Virus (HIV) Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2).

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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Epithelial proliferation and cell cycle dysregulation in kidney injury and disease

Kidney International, Journal Year: 2021, Volume and Issue: 100(1), P. 67 - 78

Published: April 6, 2021

Language: Английский

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HIV-1 Vpr drives epigenetic remodeling to enhance virus transcription and latency reactivation

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 31, 2025

Abstract Despite decades of research, the primary proviral function HIV-1 Vpr accessory protein remains enigmatic. is essential for pathogenesis in vivo and virus replication myeloid cells, but underlying cause-and-effect mechanism(s) driving these phenomena are poorly understood. Canonically, hijacks a cellular ubiquitin ligase complex to target several dozen host proteins proteasomal degradation. Many substrates were recently revealed be involved DNA damage repair (DDR), which rationalizes longstanding observation that induces constitutive activation DDR signaling. Here, we use combination functional, biochemical, genetic approaches establish clear mechanistic link between Vpr-induced signaling remodeling epigenetic landscape enhance promoter activity during acute infection reactivation from latency. Functional, genetic, bimolecular fluorescence complementation experiments reveal utilizes degradation-dependent -independent mechanisms induce segregates into two discrete pools with dedicated activities—A multimeric pool nucleus associated chromatin monomeric DCAF1 cytoplasm. nuclear environment present common subtypes worldwide provides rationale its essentiality replication. Author summary While plays an role replication, molecular remain Vpr’s best characterized ability depletion by hijacking E3-ubiquitin complex. promotes global We demonstrate linked signaling, it occurs through both mechanisms. Moreover, this circulating globally. This study novel insights how exploits pathways sheds light on function.

Language: Английский

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Applying Antibodies Inside Cells: Principles and Recent Advances in Neurobiology, Virology and Oncology

BioDrugs, Journal Year: 2020, Volume and Issue: 34(4), P. 435 - 462

Published: April 16, 2020

To interfere with cell function, many scientists rely on methods that target DNA or RNA due to the ease which they can be applied. Proteins are usually final executors of function but targeted only indirectly by these methods. Recent advances in degradation proteins based proteolysis-targeting chimaeras (PROTACs), ubiquibodies, deGradFP (degrade Green Fluorescent Protein) and other approaches have demonstrated potential interfering directly at protein level for research therapy. very specifically antibodies, using antibodies inside cells has so far been considered challenging. However, it is possible deliver into cytosol standard laboratory equipment. Physical such as electroporation efficient validated thoroughly over time. The expression intracellular (intrabodies) another way targets level. Methodological strategies including delivered expressed well applications areas neurobiology, viral infections oncology, reviewed here. Antibodies already used a wide range targets. Disease-related included associated neurodegenerative diseases Parkinson's disease (α-synuclein), Alzheimer's (amyloid-β) Huntington's (mutant huntingtin [mHtt]). intrabodies context include targeting HIV (e.g. HIV1-TAT, Rev, Vif, gp41, gp120, gp160) different oncoviruses human papillomavirus (HPV), hepatitis B virus (HBV), C (HCV) Epstein-Barr virus, various related processes cancer, oncogenic pathways, proliferation, cycle, apoptosis, metastasis, angiogenesis neo-antigens p53, epidermal growth factor receptor-2 [HER2], signal transducer activator transcription 3 [STAT3], RAS-related RHO-GTPase (RHOB), cortactin, vascular endothelial receptor 2 [VEGFR2], Ras, Bcr-Abl). Interfering allows questions addressed may remain unanswered alternative This review addresses why direct unique insights, what currently feasible vitro, how this relates therapeutic applications.

Language: Английский

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Host Restriction Factors Modulating HIV Latency and Replication in Macrophages

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(6), P. 3021 - 3021

Published: March 11, 2022

In addition to CD4+ T lymphocytes, myeloid cells and, particularly, differentiated macrophages are targets of human immunodeficiency virus type-1 (HIV-1) infection via the interaction gp120Env with CD4 and CCR5 or CXCR4. Both support replication, although substantial differences. contrast activated HIV-1 replication in occurs nondividing it is characterized by virtual absence cytopathicity both vitro vivo. These general features should be considered evaluating role cell-associated restriction factors aiming at preventing curtailing cells, particularly context designing strategies tackle viral reservoir infected individuals receiving combination antiretroviral therapy. this regard, we will here also discuss a model reversible latency primary host determining reactivation these cells.

Language: Английский

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