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Viruses
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Intrinsic Antiviral Factors
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Intrinsic Antiviral Factors

A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Viral Immunology, Vaccines, and Antivirals".

Deadline for manuscript submissions: closed (1 November 2020) | Viewed by 63197

Special Issue Editor

Dr. Sébastien Nisole

E-Mail Website
Guest Editor
Laboratory of Viral Trafficking, Restriction and Innate Signaling, Institut de Recherche en Infectiologie de Montpellier (IRIM), 1919 Route de Mende, 34090 Montpellier, France
Interests: antiviral innate immunity; interferon response; restriction factors; TRIM proteins; virus-host interactions
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cells possess all the essential factors and machineries that viruses need to achieve their replication and are therefore the victims of perpetual hostile takeovers from these parasites. This continuous selective pressure they were exposed to for millions of years has led eukaryotic cells to develop specific factors that are dedicated to antiviral defenses. These intrinsic defenses are now considered as the third arm of immunity, in addition to the traditionally bipartite immune system of innate and adaptive immunity. This notion of intrinsic immunity emerged more than 10 years ago, following the identification of cellular factors that interfere with retroviral replication, the so-called restriction factors. Since the discovery of the prototype antiretroviral restriction factors Fv1, APOBEC3G, and TRIM5a, a plethora of other intrinsic antiviral factors have been identified and interfere with the replication of many different viruses. Although they can be constitutively expressed in given cell types and thus block replication directly, most intrinsic antiviral factors are induced by interferons to amplify their antiviral activity.

Cells have thus recently emerged as new battlefields where virus and host confrontations can be witnessed first-hand, since viruses have to either escape or counteract these intracellular barriers in order to achieve their replication and ensure their propagation.

This Special Issue is intended to provide an up-to-date view of the numerous intrinsic antiviral factors that have been or are yet to be identified and the various strategies developed by viruses to evade these factors.

Dr. Sébastien Nisole
Guest Editor

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Restriction factors
  • Antiviral proteins
  • Intrinsic immunity
  • Host defense
  • Antiviral ISGs
  • Virus-cell interactions

Related Special Issue

Published Papers (19 papers)

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Research

Jump to: Review

14 pages, 3051 KiB  
Article
Impaired Antiviral Responses to Extracellular Double-Stranded RNA and Cytosolic DNA, but Not to Interferon-α Stimulation, in TRIM56-Deficient Cells
by Dang Wang, Ruixue Wang and Kui Li
Viruses 2022, 14(1), 89; https://doi.org/10.3390/v14010089 - 05 Jan 2022
Cited by 1 | Viewed by 2145
Abstract
The physiologic function of tripartite motif protein 56 (TRIM56), a ubiquitously expressed E3 ligase classified within the large TRIM protein family, remains elusive. Gene knockdown studies have suggested TRIM56 as a positive regulator of the type I interferon (IFN-I) antiviral response elicited via [...] Read more.
The physiologic function of tripartite motif protein 56 (TRIM56), a ubiquitously expressed E3 ligase classified within the large TRIM protein family, remains elusive. Gene knockdown studies have suggested TRIM56 as a positive regulator of the type I interferon (IFN-I) antiviral response elicited via the Toll-like receptor 3 (TLR3) and cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) pathways, which detect and respond to danger signals—extracellular double-stranded (ds) RNA and cytosolic dsDNA, respectively. However, to what extent these pathways depend on TRIM56 in human cells is unclear. In addition, it is debatable whether TRIM56 plays a part in controlling the expression of IFN-stimulated genes (ISGs) resulting from IFN-I based antiviral treatment. In this study, we created HeLa-derived TRIM56 null cell lines by gene editing and used these cell models to comprehensively examine the impact of endogenous TRIM56 on innate antiviral responses. Our results showed that TRIM56 knockout severely undermined the upregulation of ISGs by extracellular dsRNA and that loss of TRIM56 weakened the response to cytosolic dsDNA. ISG induction and ISGylation following IFN-α stimulation, however, were not compromised by TRIM56 deletion. Using a vesicular stomatitis virus-based antiviral bioactivity assay, we demonstrated that IFN-α could efficiently establish an antiviral state in TRIM56 null cells, providing direct evidence that TRIM56 is not required for the general antiviral action of IFN-I. Altogether, these data ascertain the contributions of TRIM56 to TLR3- and cGAS–STING-dependent antiviral pathways in HeLa cells and add to our understanding of the roles this protein plays in innate immunity. Full article
(This article belongs to the Special Issue Intrinsic Antiviral Factors)
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14 pages, 8535 KiB  
Article
Influence of Different Glycoproteins and of the Virion Core on SERINC5 Antiviral Activity
by William E. Diehl, Mehmet H. Guney, Teresa Vanzo, Pyae P. Kyawe, Judith M. White, Massimo Pizzato and Jeremy Luban
Viruses 2021, 13(7), 1279; https://doi.org/10.3390/v13071279 - 30 Jun 2021
Cited by 15 | Viewed by 2780
Abstract
Host plasma membrane protein SERINC5 is incorporated into budding retrovirus particles where it blocks subsequent entry into susceptible target cells. Three structurally unrelated proteins encoded by diverse retroviruses, human immunodeficiency virus type 1 (HIV-1) Nef, equine infectious anemia virus (EIAV) S2, and ecotropic [...] Read more.
Host plasma membrane protein SERINC5 is incorporated into budding retrovirus particles where it blocks subsequent entry into susceptible target cells. Three structurally unrelated proteins encoded by diverse retroviruses, human immunodeficiency virus type 1 (HIV-1) Nef, equine infectious anemia virus (EIAV) S2, and ecotropic murine leukemia virus (MLV) GlycoGag, disrupt SERINC5 antiviral activity by redirecting SERINC5 from the site of virion assembly on the plasma membrane to an internal RAB7+ endosomal compartment. Pseudotyping retroviruses with particular glycoproteins, e.g., vesicular stomatitis virus glycoprotein (VSV G), renders the infectivity of particles resistant to inhibition by virion-associated SERINC5. To better understand viral determinants for SERINC5-sensitivity, the effect of SERINC5 was assessed using HIV-1, MLV, and Mason-Pfizer monkey virus (M-PMV) virion cores, pseudotyped with glycoproteins from Arenavirus, Coronavirus, Filovirus, Rhabdovirus, Paramyxovirus, and Orthomyxovirus genera. SERINC5 restricted virions pseudotyped with glycoproteins from several retroviruses, an orthomyxovirus, a rhabdovirus, a paramyxovirus, and an arenavirus. Infectivity of particles pseudotyped with HIV-1, amphotropic-MLV (A-MLV), or influenza A virus (IAV) glycoproteins, was decreased by SERINC5, whether the core was provided by HIV-1, MLV, or M-PMV. In contrast, particles pseudotyped with glycoproteins from M-PMV, parainfluenza virus 5 (PIV5), or rabies virus (RABV) were sensitive to SERINC5, but only with particular retroviral cores. Resistance to SERINC5 did not correlate with reduced SERINC5 incorporation into particles, route of viral entry, or absolute infectivity of the pseudotyped virions. These findings indicate that some non-retroviruses may be sensitive to SERINC5 and that, in addition to the viral glycoprotein, the retroviral core influences sensitivity to SERINC5. Full article
(This article belongs to the Special Issue Intrinsic Antiviral Factors)
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22 pages, 7583 KiB  
Article
TRIM26 Facilitates HSV-2 Infection by Downregulating Antiviral Responses through the IRF3 Pathway
by Tushar Dhawan, Muhammad Atif Zahoor, Nishant Heryani, Samuel Tekeste Workenhe, Aisha Nazli and Charu Kaushic
Viruses 2021, 13(1), 70; https://doi.org/10.3390/v13010070 - 06 Jan 2021
Cited by 9 | Viewed by 2972
Abstract
Herpes simplex virus type 2 (HSV-2) is the primary cause of genital herpes which results in significant morbidity and mortality, especially in women, worldwide. HSV-2 is transmitted primarily through infection of epithelial cells at skin and mucosal surfaces. Our earlier work to examine [...] Read more.
Herpes simplex virus type 2 (HSV-2) is the primary cause of genital herpes which results in significant morbidity and mortality, especially in women, worldwide. HSV-2 is transmitted primarily through infection of epithelial cells at skin and mucosal surfaces. Our earlier work to examine interactions between HSV-2 and vaginal epithelial cells demonstrated that infection of the human vaginal epithelial cell line (VK2) with HSV-2 resulted in increased expression of TRIM26, a negative regulator of the Type I interferon pathway. Given that upregulation of TRIM26 could negatively affect anti-viral pathways, we decided to further study the role of TRIM26 in HSV-2 infection and replication. To do this, we designed and generated two cell lines derived from VK2s with TRIM26 overexpressed (OE) and knocked out (KO). Both, along with wildtype (WT) VK2, were infected with HSV-2 and viral titres were measured in supernatants 24 h later. Our results showed significantly enhanced virus production by TRIM26 OE cells, but very little replication in TRIM26 KO cells. We next examined interferon-β production and expression of two distinct interferon stimulated genes (ISGs), MX1 and ISG15, in all three cell lines, prior to and following HSV-2 infection. The absence of TRIM26 (KO) significantly upregulated interferon-β production at baseline and even further after HSV-2 infection. TRIM26 KO cells also showed significant increase in the expression of MX1 and ISG15 before and after HSV-2 infection. Immunofluorescent staining indicated that overexpression of TRIM26 substantially decreased the nuclear localization of IRF3, the primary mediator of ISG activation, before and after HSV-2 infection. Taken together, our data indicate that HSV-2 utilizes host factor TRIM26 to evade anti-viral response and thereby increase its replication in vaginal epithelial cells. Full article
(This article belongs to the Special Issue Intrinsic Antiviral Factors)
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14 pages, 2798 KiB  
Article
Editing of the TRIM5 Gene Decreases the Permissiveness of Human T Lymphocytic Cells to HIV-1
by Kevin Désaulniers, Levine Ortiz, Caroline Dufour, Alix Claudel, Mélodie B. Plourde, Natacha Merindol and Lionel Berthoux
Viruses 2021, 13(1), 24; https://doi.org/10.3390/v13010024 - 25 Dec 2020
Cited by 9 | Viewed by 2739
Abstract
Tripartite-motif-containing protein 5 isoform α (TRIM5α) is a cytoplasmic antiretroviral effector upregulated by type I interferons (IFN-I). We previously showed that two points mutations, R332G/R335G, in the retroviral capsid-binding region confer human TRIM5α the capacity to target and strongly restrict HIV-1 upon overexpression [...] Read more.
Tripartite-motif-containing protein 5 isoform α (TRIM5α) is a cytoplasmic antiretroviral effector upregulated by type I interferons (IFN-I). We previously showed that two points mutations, R332G/R335G, in the retroviral capsid-binding region confer human TRIM5α the capacity to target and strongly restrict HIV-1 upon overexpression of the mutated protein. Here, we used clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9-mediated homology-directed repair (HDR) to introduce these two mutations in the endogenous human TRIM5 gene. We found 6 out of 47 isolated cell clones containing at least one HDR-edited allele. One clone (clone 6) had both alleles containing R332G, but only one of the two alleles containing R335G. Upon challenge with an HIV-1 vector, clone 6 was significantly less permissive compared to unmodified cells, whereas the cell clones with monoallelic modifications were only slightly less permissive. Following interferon (IFN)-β treatment, inhibition of HIV-1 infection in clone 6 was significantly enhanced (~40-fold inhibition). TRIM5α knockdown confirmed that HIV-1 was inhibited by the edited TRIM5 gene products. Quantification of HIV-1 reverse transcription products showed that inhibition occurred through the expected mechanism. In conclusion, we demonstrate the feasibility of potently inhibiting a viral infection through the editing of innate effector genes. Our results also emphasize the importance of biallelic modification in order to reach significant levels of inhibition by TRIM5α. Full article
(This article belongs to the Special Issue Intrinsic Antiviral Factors)
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17 pages, 3087 KiB  
Article
PRRSV Vaccine Strain-Induced Secretion of Extracellular ISG15 Stimulates Porcine Alveolar Macrophage Antiviral Response against PRRSV
by Hongbin Liu, Bingjun Shi, Zhigang Zhang, Bao Zhao, Guangming Zhao, Yijing Li and Yuchen Nan
Viruses 2020, 12(9), 1009; https://doi.org/10.3390/v12091009 - 10 Sep 2020
Cited by 9 | Viewed by 2863
Abstract
Porcine reproductive and respiratory syndrome virus (PRRSV) has disrupted the global swine industry since the 1980s. PRRSV-host interactions are largely still unknown but may involve host ISG15 protein. In this study, we developed a monoclonal antibody (Mab-3D5E6) specific for swine ISG15 (sISG15) by [...] Read more.
Porcine reproductive and respiratory syndrome virus (PRRSV) has disrupted the global swine industry since the 1980s. PRRSV-host interactions are largely still unknown but may involve host ISG15 protein. In this study, we developed a monoclonal antibody (Mab-3D5E6) specific for swine ISG15 (sISG15) by immunizing mice with recombinant sISG15. A sandwich enzyme-linked immunosorbent assay (ELISA) incorporating this sISG15-specific Mab was developed to detect sISG15 and provided a lower limit of sISG15 detection of 200 pg/mL. ELISA results demonstrated that infection of porcine alveolar macrophages (PAMs) with low-virulence or attenuated PRRSV vaccine strains induced intracellular ISG15 expression that was independent of type I IFN production, while PAMs infection with a PRRSV vaccine strain promoted extracellular ISG15 secretion from infected PAMs. Conversely, the addition of recombinant sISG15 to PAMs mimicked natural extracellular ISG15 effects whereby sISG15 functioned as a cytokine by activating PAMs. Once activated, PAMs could inhibit PRRSV replication and resist infection with PRRSV vaccine strain TJM. In summary, a sandwich ELISA incorporating homemade anti-ISG15 Mab detected ISG15 secretion induced by PAMs infection with a PRRSV vaccine strain. Recombinant ISG15 added to cells exhibited cytokine-like activity that stimulated PAMs to assume an anti-viral state that enabled them to inhibit PRRSV replication and resist viral infection. Full article
(This article belongs to the Special Issue Intrinsic Antiviral Factors)
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19 pages, 1970 KiB  
Article
Daxx Inhibits HIV-1 Reverse Transcription and Uncoating in a SUMO-Dependent Manner
by Sarah Maillet, Juliette Fernandez, Mathilde Decourcelle, Khadija El Koulali, Fabien P. Blanchet, Nathalie J. Arhel, Ghizlane Maarifi and Sébastien Nisole
Viruses 2020, 12(6), 636; https://doi.org/10.3390/v12060636 - 11 Jun 2020
Cited by 9 | Viewed by 3127
Abstract
Death domain-associated protein 6 (Daxx) is a multifunctional, ubiquitously expressed and highly conserved chaperone protein involved in numerous cellular processes, including apoptosis, transcriptional repression, and carcinogenesis. In 2015, we identified Daxx as an antiretroviral factor that interfered with HIV-1 replication by inhibiting the [...] Read more.
Death domain-associated protein 6 (Daxx) is a multifunctional, ubiquitously expressed and highly conserved chaperone protein involved in numerous cellular processes, including apoptosis, transcriptional repression, and carcinogenesis. In 2015, we identified Daxx as an antiretroviral factor that interfered with HIV-1 replication by inhibiting the reverse transcription step. In the present study, we sought to unravel the molecular mechanism of Daxx-mediated restriction and, in particular, to identify the protein(s) that Daxx targets in order to achieve its antiviral activity. First, we show that the SUMO-interacting motif (SIM) located at the C-terminus of the protein is strictly required for Daxx to inhibit HIV-1 reverse transcription. By performing a quantitative proteomic screen combined with classical biochemical analyses, we found that Daxx associated with incoming HIV-1 cores through a SIM-dependent interaction with cyclophilin A (CypA) and capsid (CA). Daxx was found to reside within a multiprotein complex associated with viral capsids, also containing TNPO3, TRIM5α, and TRIM34. Given the well-known influence of these cellular factors on the stability of HIV-1 cores, we investigated the effect of Daxx on the cytoplasmic fate of incoming cores and found that Daxx prevented HIV-1 uncoating in a SIM-dependent manner. Altogether, our findings suggest that, by recruiting TNPO3, TRIM5α, and TRIM34 and possibly other proteins onto incoming HIV-1 cores through a SIM-dependent interaction with CA-bound CypA, Daxx increases their stability, thus preventing uncoating and reverse transcription. Our study uncovers a previously unknown function of Daxx in the early steps of HIV-1 infection and further illustrates how reverse transcription and uncoating are two tightly interdependent processes. Full article
(This article belongs to the Special Issue Intrinsic Antiviral Factors)
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16 pages, 2125 KiB  
Article
Polymorphisms in Human APOBEC3H Differentially Regulate Ubiquitination and Antiviral Activity
by Nicholas M. Chesarino and Michael Emerman
Viruses 2020, 12(4), 378; https://doi.org/10.3390/v12040378 - 30 Mar 2020
Cited by 13 | Viewed by 3517
Abstract
The APOBEC3 family of cytidine deaminases are an important part of the host innate immune defense against endogenous retroelements and retroviruses like Human Immunodeficiency Virus (HIV). APOBEC3H (A3H) is the most polymorphic of the human APOBEC3 genes, with four major haplotypes circulating in [...] Read more.
The APOBEC3 family of cytidine deaminases are an important part of the host innate immune defense against endogenous retroelements and retroviruses like Human Immunodeficiency Virus (HIV). APOBEC3H (A3H) is the most polymorphic of the human APOBEC3 genes, with four major haplotypes circulating in the population. Haplotype II is the only antivirally-active variant of A3H, while the majority of the population possess independently destabilizing polymorphisms present in haplotype I (R105G) and haplotypes III and IV (N15del). In this paper, we show that instability introduced by either polymorphism is positively correlated with degradative ubiquitination, while haplotype II is protected from this modification. Inhibiting ubiquitination by mutating all of the A3H lysines increased the expression of haplotypes III and IV, but these stabilized forms of haplotype III and IV had a strict nuclear localization, and did not incorporate into virions, nor exhibit antiviral activity. Fusion chimeras with haplotype II allowed for stabilization, cytoplasmic retention, and packaging of the N15del-containing haplotype III, but the haplotype III component of these chimeras was unable to restrict HIV-1 on its own. Thus, the evolutionary loss of A3H activity in many humans involves functional deficiencies independent of protein stability. Full article
(This article belongs to the Special Issue Intrinsic Antiviral Factors)
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16 pages, 8200 KiB  
Article
The N-glycosylation of Equine Tetherin Affects Antiviral Activity by Regulating Its Subcellular Localization
by Bowen Bai, Xue-Feng Wang, Mengmeng Zhang, Lei Na, Xiangmin Zhang, Haili Zhang, Zhibiao Yang and Xiaojun Wang
Viruses 2020, 12(2), 220; https://doi.org/10.3390/v12020220 - 16 Feb 2020
Cited by 6 | Viewed by 2108
Abstract
Tetherin is an interferon-inducible type II transmembrane glycoprotein which inhibits the release of viruses, including retroviruses, through a “physical tethering” model. However, the role that the glycosylation of tetherin plays in its antiviral activity remains controversial. In this study, we found that mutation [...] Read more.
Tetherin is an interferon-inducible type II transmembrane glycoprotein which inhibits the release of viruses, including retroviruses, through a “physical tethering” model. However, the role that the glycosylation of tetherin plays in its antiviral activity remains controversial. In this study, we found that mutation of N-glycosylation sites resulted in an attenuation of the antiviral activity of equine tetherin (eqTHN), as well as a reduction in the expression of eqTHN at the plasma membrane (PM). In addition, eqTHN N-glycosylation mutants colocalize obviously with ER, CD63, LAMP1 and endosomes, while WT eqTHN do not. Furthermore, we also found that N-glycosylation impacts the transport of eqTHN in the cell not by affecting the endocytosis, but rather by influencing the anterograde trafficking of the protein. These results suggest that the N-glycosylation of eqTHN is important for the antiviral activity of the protein through regulating its normal subcellular localization. This finding will enhance our understanding of the function of this important restriction factor. Full article
(This article belongs to the Special Issue Intrinsic Antiviral Factors)
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12 pages, 2880 KiB  
Article
TRIM41-Mediated Ubiquitination of Nucleoprotein Limits Vesicular Stomatitis Virus Infection
by Girish Patil, Lingling Xu, Yakun Wu, Kun Song, Wenzhuo Hao, Fang Hua, Lingyan Wang and Shitao Li
Viruses 2020, 12(2), 131; https://doi.org/10.3390/v12020131 - 22 Jan 2020
Cited by 20 | Viewed by 3749
Abstract
Vesicular stomatitis virus (VSV) is a zoonotic, negative-stranded RNA virus of the family Rhabdoviridae. The nucleoprotein (N) of VSV protects the viral genomic RNA and plays an essential role in viral transcription and replication, which makes the nucleoprotein an ideal target of host [...] Read more.
Vesicular stomatitis virus (VSV) is a zoonotic, negative-stranded RNA virus of the family Rhabdoviridae. The nucleoprotein (N) of VSV protects the viral genomic RNA and plays an essential role in viral transcription and replication, which makes the nucleoprotein an ideal target of host defense. However, whether and how host innate/intrinsic immunity limits VSV infection by targeting the N protein are unknown. In this study, we found that the N protein of VSV (VSV-N) interacted with a ubiquitin E3 ligase, tripartite motif protein 41 (TRIM41). Overexpression of TRIM41 inhibited VSV infection. Conversely, the depletion of TRIM41 increased host susceptibility to VSV. Furthermore, the E3 ligase defective mutant of TRIM41 failed to limit VSV infection, suggesting the requirement of the E3 ligase activity of TRIM41 in viral restriction. Indeed, TRIM41 ubiquitinated VSV-N in cells and in vitro. TRIM41-mediated ubiquitination leads to the degradation of VSV-N through proteasome, thereby limiting VSV infection. Taken together, our study identifies TRIM41 as a new intrinsic immune factor against VSV by targeting the viral nucleoprotein for ubiquitination and subsequent protein degradation. Full article
(This article belongs to the Special Issue Intrinsic Antiviral Factors)
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Review

Jump to: Research

26 pages, 2391 KiB  
Review
Regulation of Viral Restriction by Post-Translational Modifications
by Célia Chamontin, Guillaume Bossis, Sébastien Nisole, Nathalie J. Arhel and Ghizlane Maarifi
Viruses 2021, 13(11), 2197; https://doi.org/10.3390/v13112197 - 01 Nov 2021
Cited by 7 | Viewed by 3723
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Intrinsic Antiviral Factors)
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37 pages, 2522 KiB  
Review
Immunity and Viral Infections: Modulating Antiviral Response via CRISPR–Cas Systems
by Sergey Brezgin, Anastasiya Kostyusheva, Ekaterina Bayurova, Elena Volchkova, Vladimir Gegechkori, Ilya Gordeychuk, Dieter Glebe, Dmitry Kostyushev and Vladimir Chulanov
Viruses 2021, 13(7), 1373; https://doi.org/10.3390/v13071373 - 15 Jul 2021
Cited by 11 | Viewed by 4916
Abstract
Viral infections cause a variety of acute and chronic human diseases, sometimes resulting in small local outbreaks, or in some cases spreading across the globe and leading to global pandemics. Understanding and exploiting virus–host interactions is instrumental for identifying host factors involved in [...] Read more.
Viral infections cause a variety of acute and chronic human diseases, sometimes resulting in small local outbreaks, or in some cases spreading across the globe and leading to global pandemics. Understanding and exploiting virus–host interactions is instrumental for identifying host factors involved in viral replication, developing effective antiviral agents, and mitigating the severity of virus-borne infectious diseases. The diversity of CRISPR systems and CRISPR-based tools enables the specific modulation of innate immune responses and has contributed impressively to the fields of virology and immunology in a very short time. In this review, we describe the most recent advances in the use of CRISPR systems for basic and translational studies of virus–host interactions. Full article
(This article belongs to the Special Issue Intrinsic Antiviral Factors)
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14 pages, 1491 KiB  
Review
The Antiviral Activities of Poly-ADP-Ribose Polymerases
by Mathilde Malgras, Magali Garcia, Clément Jousselin, Charles Bodet and Nicolas Lévêque
Viruses 2021, 13(4), 582; https://doi.org/10.3390/v13040582 - 30 Mar 2021
Cited by 23 | Viewed by 3032
Abstract
The poly-adenosine diphosphate (ADP)-ribose polymerases (PARPs) are responsible for ADP-ribosylation, a reversible post-translational modification involved in many cellular processes including DNA damage repair, chromatin remodeling, regulation of translation and cell death. In addition to these physiological functions, recent studies have highlighted the role [...] Read more.
The poly-adenosine diphosphate (ADP)-ribose polymerases (PARPs) are responsible for ADP-ribosylation, a reversible post-translational modification involved in many cellular processes including DNA damage repair, chromatin remodeling, regulation of translation and cell death. In addition to these physiological functions, recent studies have highlighted the role of PARPs in host defenses against viruses, either by direct antiviral activity, targeting certain steps of virus replication cycle, or indirect antiviral activity, via modulation of the innate immune response. This review focuses on the antiviral activity of PARPs, as well as strategies developed by viruses to escape their action. Full article
(This article belongs to the Special Issue Intrinsic Antiviral Factors)
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38 pages, 2208 KiB  
Review
Mammalian and Avian Host Cell Influenza A Restriction Factors
by Joe McKellar, Antoine Rebendenne, Mélanie Wencker, Olivier Moncorgé and Caroline Goujon
Viruses 2021, 13(3), 522; https://doi.org/10.3390/v13030522 - 22 Mar 2021
Cited by 12 | Viewed by 4801
Abstract
The threat of a new influenza pandemic is real. With past pandemics claiming millions of lives, finding new ways to combat this virus is essential. Host cells have developed a multi-modular system to detect incoming pathogens, a phenomenon called sensing. The signaling cascade [...] Read more.
The threat of a new influenza pandemic is real. With past pandemics claiming millions of lives, finding new ways to combat this virus is essential. Host cells have developed a multi-modular system to detect incoming pathogens, a phenomenon called sensing. The signaling cascade triggered by sensing subsequently induces protection for themselves and their surrounding neighbors, termed interferon (IFN) response. This response induces the upregulation of hundreds of interferon-stimulated genes (ISGs), including antiviral effectors, establishing an antiviral state. As well as the antiviral proteins induced through the IFN system, cells also possess a so-called intrinsic immunity, constituted of antiviral proteins that are constitutively expressed, creating a first barrier preceding the induction of the interferon system. All these combined antiviral effectors inhibit the virus at various stages of the viral lifecycle, using a wide array of mechanisms. Here, we provide a review of mammalian and avian influenza A restriction factors, detailing their mechanism of action and in vivo relevance, when known. Understanding their mode of action might help pave the way for the development of new influenza treatments, which are absolutely required if we want to be prepared to face a new pandemic. Full article
(This article belongs to the Special Issue Intrinsic Antiviral Factors)
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21 pages, 2135 KiB  
Review
Host Components That Modulate the Disease Caused by hMPV
by Nicolás M. S. Gálvez, Catalina A. Andrade, Gaspar A. Pacheco, Jorge A. Soto, Vicente Stranger, Thomas Rivera, Abel E. Vásquez and Alexis M. Kalergis
Viruses 2021, 13(3), 519; https://doi.org/10.3390/v13030519 - 22 Mar 2021
Cited by 9 | Viewed by 2629
Abstract
Human metapneumovirus (hMPV) is one of the main pathogens responsible for acute respiratory infections in children up to 5 years of age, contributing substantially to health burden. The worldwide economic and social impact of this virus is significant and must be addressed. The [...] Read more.
Human metapneumovirus (hMPV) is one of the main pathogens responsible for acute respiratory infections in children up to 5 years of age, contributing substantially to health burden. The worldwide economic and social impact of this virus is significant and must be addressed. The structural components of hMPV (either proteins or genetic material) can be detected by several receptors expressed by host cells through the engagement of pattern recognition receptors. The recognition of the structural components of hMPV can promote the signaling of the immune response to clear the infection, leading to the activation of several pathways, such as those related to the interferon response. Even so, several intrinsic factors are capable of modulating the immune response or directly inhibiting the replication of hMPV. This article will discuss the current knowledge regarding the innate and adaptive immune response during hMPV infections. Accordingly, the host intrinsic components capable of modulating the immune response and the elements capable of restricting viral replication during hMPV infections will be examined. Full article
(This article belongs to the Special Issue Intrinsic Antiviral Factors)
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8 pages, 1148 KiB  
Review
From Capsids to Complexes: Expanding the Role of TRIM5α in the Restriction of Divergent RNA Viruses and Elements
by Kevin M. Rose, Stephanie J. Spada, Rebecca Broeckel, Kristin L. McNally, Vanessa M. Hirsch, Sonja M. Best and Fadila Bouamr
Viruses 2021, 13(3), 446; https://doi.org/10.3390/v13030446 - 10 Mar 2021
Cited by 7 | Viewed by 2332
Abstract
An evolutionary arms race has been ongoing between retroviruses and their primate hosts for millions of years. Within the last century, a zoonotic transmission introduced the Human Immunodeficiency Virus (HIV-1), a retrovirus, to the human population that has claimed the lives of millions [...] Read more.
An evolutionary arms race has been ongoing between retroviruses and their primate hosts for millions of years. Within the last century, a zoonotic transmission introduced the Human Immunodeficiency Virus (HIV-1), a retrovirus, to the human population that has claimed the lives of millions of individuals and is still infecting over a million people every year. To counteract retroviruses such as this, primates including humans have evolved an innate immune sensor for the retroviral capsid lattice known as TRIM5α. Although the molecular basis for its ability to restrict retroviruses is debated, it is currently accepted that TRIM5α forms higher-order assemblies around the incoming retroviral capsid that are not only disruptive for the virus lifecycle, but also trigger the activation of an antiviral state. More recently, it was discovered that TRIM5α restriction is broader than previously thought because it restricts not only the human retroelement LINE-1, but also the tick-borne flaviviruses, an emergent group of RNA viruses that have vastly different strategies for replication compared to retroviruses. This review focuses on the underlying mechanisms of TRIM5α-mediated restriction of retroelements and flaviviruses and how they differ from the more widely known ability of TRIM5α to restrict retroviruses. Full article
(This article belongs to the Special Issue Intrinsic Antiviral Factors)
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16 pages, 934 KiB  
Review
SAMHD1 … and Viral Ways around It
by Janina Deutschmann and Thomas Gramberg
Viruses 2021, 13(3), 395; https://doi.org/10.3390/v13030395 - 02 Mar 2021
Cited by 13 | Viewed by 3022
Abstract
The SAM and HD domain-containing protein 1 (SAMHD1) is a dNTP triphosphohydrolase that plays a crucial role for a variety of different cellular functions. Besides balancing intracellular dNTP concentrations, facilitating DNA damage repair, and dampening excessive immune responses, SAMHD1 has been shown to [...] Read more.
The SAM and HD domain-containing protein 1 (SAMHD1) is a dNTP triphosphohydrolase that plays a crucial role for a variety of different cellular functions. Besides balancing intracellular dNTP concentrations, facilitating DNA damage repair, and dampening excessive immune responses, SAMHD1 has been shown to act as a major restriction factor against various virus species. In addition to its well-described activity against retroviruses such as HIV-1, SAMHD1 has been identified to reduce the infectivity of different DNA viruses such as the herpesviruses CMV and EBV, the poxvirus VACV, or the hepadnavirus HBV. While some viruses are efficiently restricted by SAMHD1, others have developed evasion mechanisms that antagonize the antiviral activity of SAMHD1. Within this review, we summarize the different cellular functions of SAMHD1 and highlight the countermeasures viruses have evolved to neutralize the restriction factor SAMHD1. Full article
(This article belongs to the Special Issue Intrinsic Antiviral Factors)
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32 pages, 2901 KiB  
Review
Human TRIM5α: Autophagy Connects Cell-Intrinsic HIV-1 Restriction and Innate Immune Sensor Functioning
by Alexandra P. M. Cloherty, Anusca G. Rader, Brandon Compeer and Carla M. S. Ribeiro
Viruses 2021, 13(2), 320; https://doi.org/10.3390/v13020320 - 19 Feb 2021
Cited by 11 | Viewed by 4410
Abstract
Human immunodeficiency virus-1 (HIV-1) persists as a global health concern, with an incidence rate of approximately 2 million, and estimated global prevalence of over 35 million. Combination antiretroviral treatment is highly effective, but HIV-1 patients that have been treated still suffer from chronic [...] Read more.
Human immunodeficiency virus-1 (HIV-1) persists as a global health concern, with an incidence rate of approximately 2 million, and estimated global prevalence of over 35 million. Combination antiretroviral treatment is highly effective, but HIV-1 patients that have been treated still suffer from chronic inflammation and residual viral replication. It is therefore paramount to identify therapeutically efficacious strategies to eradicate viral reservoirs and ultimately develop a cure for HIV-1. It has been long accepted that the restriction factor tripartite motif protein 5 isoform alpha (TRIM5α) restricts HIV-1 infection in a species-specific manner, with rhesus macaque TRIM5α strongly restricting HIV-1, and human TRIM5α having a minimal restriction capacity. However, several recent studies underscore human TRIM5α as a cell-dependent HIV-1 restriction factor. Here, we present an overview of the latest research on human TRIM5α and propose a novel conceptualization of TRIM5α as a restriction factor with a varied portfolio of antiviral functions, including mediating HIV-1 degradation through autophagy- and proteasome-mediated mechanisms, and acting as a viral sensor and effector of antiviral signaling. We have also expanded on the protective antiviral roles of autophagy and outline the therapeutic potential of autophagy modulation to intervene in chronic HIV-1 infection. Full article
(This article belongs to the Special Issue Intrinsic Antiviral Factors)
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17 pages, 3865 KiB  
Review
Emerging Role of PYHIN Proteins as Antiviral Restriction Factors
by Matteo Bosso and Frank Kirchhoff
Viruses 2020, 12(12), 1464; https://doi.org/10.3390/v12121464 - 18 Dec 2020
Cited by 10 | Viewed by 3387
Abstract
Innate immune sensors and restriction factors are cellular proteins that synergize to build an effective first line of defense against viral infections. Innate sensors are usually constitutively expressed and capable of detecting pathogen-associated molecular patterns (PAMPs) via specific pattern recognition receptors (PRRs) to [...] Read more.
Innate immune sensors and restriction factors are cellular proteins that synergize to build an effective first line of defense against viral infections. Innate sensors are usually constitutively expressed and capable of detecting pathogen-associated molecular patterns (PAMPs) via specific pattern recognition receptors (PRRs) to stimulate the immune response. Restriction factors are frequently upregulated by interferons (IFNs) and may inhibit viral pathogens at essentially any stage of their replication cycle. Members of the Pyrin and hematopoietic interferon-inducible nuclear (HIN) domain (PYHIN) family have initially been recognized as important sensors of foreign nucleic acids and activators of the inflammasome and the IFN response. Accumulating evidence shows, however, that at least three of the four members of the human PYHIN family restrict viral pathogens independently of viral sensing and innate immune activation. In this review, we provide an overview on the role of human PYHIN proteins in the innate antiviral immune defense and on viral countermeasures. Full article
(This article belongs to the Special Issue Intrinsic Antiviral Factors)
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20 pages, 1018 KiB  
Review
Host Cell Restriction Factors of Paramyxoviruses and Pneumoviruses
by Rubaiyea Farrukee, Malika Ait-Goughoulte, Philippa M. Saunders, Sarah L. Londrigan and Patrick C. Reading
Viruses 2020, 12(12), 1381; https://doi.org/10.3390/v12121381 - 02 Dec 2020
Cited by 5 | Viewed by 3100
Abstract
The paramyxo- and pneumovirus family includes a wide range of viruses that can cause respiratory and/or systemic infections in humans and animals. The significant disease burden of these viruses is further exacerbated by the limited therapeutics that are currently available. Host cellular proteins [...] Read more.
The paramyxo- and pneumovirus family includes a wide range of viruses that can cause respiratory and/or systemic infections in humans and animals. The significant disease burden of these viruses is further exacerbated by the limited therapeutics that are currently available. Host cellular proteins that can antagonize or limit virus replication are therefore a promising area of research to identify candidate molecules with the potential for host-targeted therapies. Host proteins known as host cell restriction factors are constitutively expressed and/or induced in response to virus infection and include proteins from interferon-stimulated genes (ISGs). Many ISG proteins have been identified but relatively few have been characterized in detail and most studies have focused on studying their antiviral activities against particular viruses, such as influenza A viruses and human immunodeficiency virus (HIV)-1. This review summarizes current literature regarding host cell restriction factors against paramyxo- and pneumoviruses, on which there is more limited data. Alongside discussion of known restriction factors, this review also considers viral countermeasures in overcoming host restriction, the strengths and limitations in different experimental approaches in studies reported to date, and the challenges in reconciling differences between in vitro and in vivo data. Furthermore, this review provides an outlook regarding the landscape of emerging technologies and tools available to study host cell restriction factors, as well as the suitability of these proteins as targets for broad-spectrum antiviral therapeutics. Full article
(This article belongs to the Special Issue Intrinsic Antiviral Factors)
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