scholarly journals Cellular Cullin RING Ubiquitin Ligases: Druggable Host Dependency Factors of Cytomegaloviruses

2019 ◽  
Vol 20 (7) ◽  
pp. 1636 ◽  
Author(s):  
Tanja Becker ◽  
Vu Le-Trilling ◽  
Mirko Trilling
Keyword(s):  
Drug Targets ◽  
Current Knowledge ◽  
Antiviral Treatment ◽  
Term Therapy ◽  
Restriction Factors ◽  
Intrinsic Immunity ◽  
Host Restriction ◽  
Host Restriction Factors ◽  
Inhibitory Compound ◽  
Long Term Therapy

Human cytomegalovirus (HCMV) is a ubiquitous betaherpesvirus that frequently causes morbidity and mortality in individuals with insufficient immunity, such as transplant recipients, AIDS patients, and congenitally infected newborns. Several antiviral drugs are approved to treat HCMV infections. However, resistant HCMV mutants can arise in patients receiving long-term therapy. Additionally, side effects and the risk to cause birth defects limit the use of currently approved antivirals against HCMV. Therefore, the identification of new drug targets is of clinical relevance. Recent work identified DNA-damage binding protein 1 (DDB1) and the family of the cellular cullin (Cul) RING ubiquitin (Ub) ligases (CRLs) as host-derived factors that are relevant for the replication of human and mouse cytomegaloviruses. The first-in-class CRL inhibitory compound Pevonedistat (also called MLN4924) is currently under investigation as an anti-tumor drug in several clinical trials. Cytomegaloviruses exploit CRLs to regulate the abundance of viral proteins, and to induce the proteasomal degradation of host restriction factors involved in innate and intrinsic immunity. Accordingly, pharmacological blockade of CRL activity diminishes viral replication in cell culture. In this review, we summarize the current knowledge concerning the relevance of DDB1 and CRLs during cytomegalovirus replication and discuss chances and drawbacks of CRL inhibitory drugs as potential antiviral treatment against HCMV.

scholarly journals Cell Entry of Animal Coronaviruses

Viruses ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 1977
Author(s):  
Yang-Ran Cheng ◽  
Xinglin Li ◽  
Xuesen Zhao ◽  
Hanxin Lin
Keyword(s):  
Membrane Fusion ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Cell Entry ◽  
Interspecies Transmission ◽  
Restriction Factors ◽  
Cell Binding ◽  
Host Restriction ◽  
Host Restriction Factors ◽  
Made In

Coronaviruses (CoVs) are a group of enveloped positive-sense RNA viruses and can cause deadly diseases in animals and humans. Cell entry is the first and essential step of successful virus infection and can be divided into two ongoing steps: cell binding and membrane fusion. Over the past two decades, stimulated by the global outbreak of SARS-CoV and pandemic of SARS-CoV-2, numerous efforts have been made in the CoV research. As a result, significant progress has been achieved in our understanding of the cell entry process. Here, we review the current knowledge of this essential process, including the viral and host components involved in cell binding and membrane fusion, molecular mechanisms of their interactions, and the sites of virus entry. We highlight the recent findings of host restriction factors that inhibit CoVs entry. This knowledge not only enhances our understanding of the cell entry process, pathogenesis, tissue tropism, host range, and interspecies-transmission of CoVs but also provides a theoretical basis to design effective preventive and therapeutic strategies to control CoVs infection.

scholarly journals Foamy Viruses, Bet, and APOBEC3 Restriction

Viruses ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 504
Author(s):  
Ananda Ayyappan Jaguva Vasudevan ◽  
Daniel Becker ◽  
Tom Luedde ◽  
Holger Gohlke ◽  
Carsten Münk
Keyword(s):  
Current Knowledge ◽  
Regulatory Protein ◽  
Host Population ◽  
Life Cycles ◽  
Restriction Factors ◽  
Host Restriction ◽  
Open Questions ◽  
Foamy Viruses ◽  
Natural Hosts ◽  
Hiv 1

Non-human primates (NHP) are an important source of viruses that can spillover to humans and, after adaptation, spread through the host population. Whereas HIV-1 and HTLV-1 emerged as retroviral pathogens in humans, a unique class of retroviruses called foamy viruses (FV) with zoonotic potential are occasionally detected in bushmeat hunters or zookeepers. Various FVs are endemic in numerous mammalian natural hosts, such as primates, felines, bovines, and equines, and other animals, but not in humans. They are apathogenic, and significant differences exist between the viral life cycles of FV and other retroviruses. Importantly, FVs replicate in the presence of many well-defined retroviral restriction factors such as TRIM5α, BST2 (Tetherin), MX2, and APOBEC3 (A3). While the interaction of A3s with HIV-1 is well studied, the escape mechanisms of FVs from restriction by A3 is much less explored. Here we review the current knowledge of FV biology, host restriction factors, and FV–host interactions with an emphasis on the consequences of FV regulatory protein Bet binding to A3s and outline crucial open questions for future studies.

Sequence analysis identified an HTLV-1 subtype and mutations of host restriction factors susceptible to HAM/TSP

2017 ◽  
Vol 381 ◽  
pp. 1006
Author(s):  
S. Nozuma ◽  
E. Matsuura ◽  
T. Matsuzaki ◽  
D. Kodama ◽  
R. Kubota ◽  
...  
Keyword(s):  
Sequence Analysis ◽  
Restriction Factors ◽  
Host Restriction ◽  
Host Restriction Factors

Amphotericin b effect on the sensitivity to influenza infection of WI-38 VA-13 cells with IFITM3 gene knockout

2021 ◽  
Vol 21 (3) ◽  
pp. 109-112
Author(s):  
Kira S. Koryabina ◽  
Mariya V. Sergeeva ◽  
Andrey B. Komissarov ◽  
Nataliya V. Eshchenko ◽  
Grigoriy A. Stepanov
Keyword(s):  
Amphotericin B ◽  
Influenza A Virus ◽  
Influenza A ◽  
Gene Knockout ◽  
Influenza Infection ◽  
Restriction Factors ◽  
Host Restriction ◽  
Host Restriction Factors ◽  
Infected Cells ◽  
The Difference

BACKGROUND: The application of CRISPR/Cas9 is one of the most rapidly developing areas in biotechnology. This method was used to obtain clones of а human origin cell line with knockout of one or more genes of the IFITM family, representing host restriction factors for influenza infection. Amphotericin B has previously been shown to promote influenza infection by blocking IFITM3 function. AIM: The aim of this study was to evaluate the effect of amphotericin B on the sensitivity of IFITM knockout cells to influenza A virus infection. MATERIALS AND METHODS: WI-38 VA-13 cells and mutant clones with IFITM3 knockout (F3 clone) or IFITM1, IFITM3 knockout (clone E12) were infected with influenza virus A/PR/8/34 (H1N1) in the presence or absence of amphotericin B. Forty-four hours after infection, the culture medium was taken to determine the infectious activity of the virus by titration in the MDCK cell culture, as well as the hemagglutinating activity of the virus. The infected cells were stained with fluorescently labeled antibodies against the viral NP protein, and the number of NP-positive cells was determined by flow cytometry. RESULTS: The addition of amphotericin B increased the hemagglutinating and infectious activity of the virus in WI-38 VA-13cells, while the difference was insignificant for clones with IFITM gene knockout. A similar dependency was obtained for the percent of infected cells. CONCLUSIONS: Mutant cells with a knockout of one or several genes of the IFITM family were equally susceptible to influenza infection regardless of the addition of amphotericin B, which confirms the crucial importance of a defect in the IFITM3 protein in increasing the permissiveness of cells to influenza A virus.

Host Restriction Factors and Human Immunodeficiency Virus (HIV-1): A Dynamic Interplay Involving All Phases of the Viral Life Cycle

2018 ◽  
Vol 16 (3) ◽  
pp. 184-207 ◽  
Author(s):  
Vanessa D`Urbano ◽  
Elisa De Crignis ◽  
Maria Carla Re
Keyword(s):  
Mammalian Cells ◽  
Viral Evolution ◽  
Type I ◽  
Restriction Factors ◽  
Host Restriction ◽  
Host Restriction Factors ◽  
Immunodeficiency Virus ◽  
Lentiviral Infection ◽  
Specific Proteins ◽  
Hiv 1

Mammalian cells have evolved several mechanisms to prevent or block lentiviral infection and spread. Among the innate immune mechanisms, the signaling cascade triggered by type I interferon (IFN) plays a pivotal role in limiting the burden of HIV-1. In the presence of IFN, human cells upregulate the expression of a number of genes, referred to as IFN-stimulated genes (ISGs), many of them acting as antiviral restriction factors (RFs). RFs are dominant proteins that target different essential steps of the viral cycle, thereby providing an early line of defense against the virus. The identification and characterization of RFs have provided unique insights into the molecular biology of HIV-1, further revealing the complex host-pathogen interplay that characterizes the infection. The presence of RFs drove viral evolution, forcing the virus to develop specific proteins to counteract their activity. The knowledge of the mechanisms that prevent viral infection and their viral counterparts may offer new insights to improve current antiviral strategies. This review provides an overview of the RFs targeting HIV-1 replication and the mechanisms that regulate their expression as well as their impact on viral replication and the clinical course of the disease.

scholarly journals Regulation of Viral Restriction by Post-Translational Modifications

Viruses ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2197
Author(s):  
Célia Chamontin ◽  
Guillaume Bossis ◽  
Sébastien Nisole ◽  
Nathalie J. Arhel ◽  
Ghizlane Maarifi
Keyword(s):  
Viral Replication ◽  
Defense Mechanisms ◽  
Current Knowledge ◽  
Restriction Factors ◽  
Intrinsic Immunity ◽  
Post Translational Modifications ◽  
Major Mechanism ◽  
Wide Range ◽  
Subsequent Degradation ◽  
Global Vision

Intrinsic immunity is orchestrated by a wide range of host cellular proteins called restriction factors. They have the capacity to interfere with viral replication, and most of them are tightly regulated by interferons (IFNs). In addition, their regulation through post-translational modifications (PTMs) constitutes a major mechanism to shape their action positively or negatively. Following viral infection, restriction factor modification can be decisive. Palmitoylation of IFITM3, SUMOylation of MxA, SAMHD1 and TRIM5α or glycosylation of BST2 are some of those PTMs required for their antiviral activity. Nonetheless, for their benefit and by manipulating the PTMs machinery, viruses have evolved sophisticated mechanisms to counteract restriction factors. Indeed, many viral proteins evade restriction activity by inducing their ubiquitination and subsequent degradation. Studies on PTMs and their substrates are essential for the understanding of the antiviral defense mechanisms and provide a global vision of all possible regulations of the immune response at a given time and under specific infection conditions. Our aim was to provide an overview of current knowledge regarding the role of PTMs on restriction factors with an emphasis on their impact on viral replication.

scholarly journals Epigenetic factor siRNA screen during primary KSHV infection identifies novel host restriction factors for the lytic cycle of KSHV

2020 ◽  
Vol 16 (1) ◽  
pp. e1008268 ◽  
Author(s):  
Nenavath Gopal Naik ◽  
Thomas Hong Nguyen ◽  
Lauren Roberts ◽  
Luke Todd Fischer ◽  
Katherine Glickman ◽  
...  
Keyword(s):  
Lytic Cycle ◽  
Restriction Factors ◽  
Sirna Screen ◽  
Kshv Infection ◽  
Host Restriction ◽  
Host Restriction Factors ◽  
Epigenetic Factor ◽  
Novel Host

scholarly journals A pooled genome-wide screening strategy to identify and rank influenza host restriction factors in cell-based vaccine production platforms

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
David M. Sharon ◽  
Sean Nesdoly ◽  
Hsin J. Yang ◽  
Jean-François Gélinas ◽  
Yu Xia ◽  
...  
Keyword(s):  
Screening Strategy ◽  
Vaccine Production ◽  
Restriction Factors ◽  
Host Restriction ◽  
Host Restriction Factors ◽  
Genome Wide

Characterization of porcine tripartite motif genes as host restriction factors against PRRSV and PEDV infection

2019 ◽  
Vol 270 ◽  
pp. 197647 ◽  
Author(s):  
Ying Wei ◽  
Chuangchao Zou ◽  
Siying Zeng ◽  
Chunyi Xue ◽  
Yongchang Cao
Keyword(s):  
Restriction Factors ◽  
Host Restriction ◽  
Host Restriction Factors ◽  
Tripartite Motif
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