Review

24 pages, 5673 KiB

Open AccessReview

Norovirus Protease Structure and Antivirals Development

by Boyang Zhao, Liya Hu, Yongcheng Song, Ketki Patil, Sasirekha Ramani, Robert L. Atmar, Mary K. Estes and B. V. Venkataram Prasad

Viruses 2021, 13(10), 2069; https://doi.org/10.3390/v13102069 - 14 Oct 2021

Cited by 3 | Viewed by 3343

Abstract

Human norovirus (HuNoV) infection is a global health and economic burden. Currently, there are no licensed HuNoV vaccines or antiviral drugs available. The protease encoded by the HuNoV genome plays a critical role in virus replication by cleaving the polyprotein and is an [...] Read more.

Human norovirus (HuNoV) infection is a global health and economic burden. Currently, there are no licensed HuNoV vaccines or antiviral drugs available. The protease encoded by the HuNoV genome plays a critical role in virus replication by cleaving the polyprotein and is an excellent target for developing small-molecule inhibitors. The current strategy for developing HuNoV protease inhibitors is by targeting the enzyme’s active site and designing inhibitors that bind to the substrate-binding pockets located near the active site. However, subtle differential conformational flexibility in response to the different substrates in the polyprotein and structural differences in the active site and substrate-binding pockets across different genogroups, hamper the development of effective broad-spectrum inhibitors. A comparative analysis of the available HuNoV protease structures may provide valuable insight for identifying novel strategies for the design and development of such inhibitors. The goal of this review is to provide such analysis together with an overview of the current status of the design and development of HuNoV protease inhibitors. Full article

(This article belongs to the Special Issue Viruses Ten-Year Anniversary)

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19 pages, 1665 KiB

Open AccessReview

Virus Infection Variability by Single-Cell Profiling

by Maarit Suomalainen and Urs F. Greber

Viruses 2021, 13(8), 1568; https://doi.org/10.3390/v13081568 - 09 Aug 2021

Cited by 17 | Viewed by 10190

Abstract

Cell-to-cell variability of infection has long been known, yet it has remained one of the least understood phenomena in infection research. It impacts on disease onset and development, yet only recently underlying mechanisms have been studied in clonal cell cultures by single-virion immunofluorescence [...] Read more.

Cell-to-cell variability of infection has long been known, yet it has remained one of the least understood phenomena in infection research. It impacts on disease onset and development, yet only recently underlying mechanisms have been studied in clonal cell cultures by single-virion immunofluorescence microscopy and flow cytometry. In this review, we showcase how single-cell RNA sequencing (scRNA-seq), single-molecule RNA-fluorescence in situ hybridization (FISH), and copper(I)-catalyzed azide-alkyne cycloaddition (click) with alkynyl-tagged viral genomes dissect infection variability in human and mouse cells. We show how the combined use of scRNA-FISH and click-chemistry reveals highly variable onsets of adenoviral gene expression, and how single live cell plaques reveal lytic and nonlytic adenovirus transmissions. The review highlights how scRNA-seq profiling and scRNA-FISH of coxsackie, influenza, dengue, zika, and herpes simplex virus infections uncover transcriptional variability, and how the host interferon response tunes influenza and sendai virus infections. We introduce the concept of “cell state” in infection variability, and conclude with advances by single-cell simultaneous measurements of chromatin accessibility and mRNA counts at high-throughput. Such technology will further dissect the sequence of events in virus infection and pathology, and better characterize the genetic and genomic stability of viruses, cell autonomous innate immune responses, and mechanisms of tissue injury. Full article

(This article belongs to the Special Issue Viruses Ten-Year Anniversary)

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51 pages, 11314 KiB

Open AccessReview

NMR Studies of Retroviral Genome Packaging

by Patricia S. Boyd, Janae B. Brown, Joshua D. Brown, Jonathan Catazaro, Issac Chaudry, Pengfei Ding, Xinmei Dong, Jan Marchant, Colin T. O’Hern, Karndeep Singh, Canessa Swanson, Michael F. Summers and Saif Yasin

Viruses 2020, 12(10), 1115; https://doi.org/10.3390/v12101115 - 30 Sep 2020

Cited by 5 | Viewed by 4735 | Correction

Abstract

Nearly all retroviruses selectively package two copies of their unspliced RNA genomes from a cellular milieu that contains a substantial excess of non-viral and spliced viral RNAs. Over the past four decades, combinations of genetic experiments, phylogenetic analyses, nucleotide accessibility mapping, in silico [...] Read more.

Nearly all retroviruses selectively package two copies of their unspliced RNA genomes from a cellular milieu that contains a substantial excess of non-viral and spliced viral RNAs. Over the past four decades, combinations of genetic experiments, phylogenetic analyses, nucleotide accessibility mapping, in silico RNA structure predictions, and biophysical experiments were employed to understand how retroviral genomes are selected for packaging. Genetic studies provided early clues regarding the protein and RNA elements required for packaging, and nucleotide accessibility mapping experiments provided insights into the secondary structures of functionally important elements in the genome. Three-dimensional structural determinants of packaging were primarily derived by nuclear magnetic resonance (NMR) spectroscopy. A key advantage of NMR, relative to other methods for determining biomolecular structure (such as X-ray crystallography), is that it is well suited for studies of conformationally dynamic and heterogeneous systems—a hallmark of the retrovirus packaging machinery. Here, we review advances in understanding of the structures, dynamics, and interactions of the proteins and RNA elements involved in retroviral genome selection and packaging that are facilitated by NMR. Full article

(This article belongs to the Special Issue Viruses Ten-Year Anniversary)

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32 pages, 5737 KiB

Open AccessReview

HIV-1 Maturation: Lessons Learned from Inhibitors

by Alex B. Kleinpeter and Eric O. Freed

Viruses 2020, 12(9), 940; https://doi.org/10.3390/v12090940 - 26 Aug 2020

Cited by 56 | Viewed by 8800

Abstract

Since the emergence of HIV and AIDS in the early 1980s, the development of safe and effective therapies has accompanied a massive increase in our understanding of the fundamental processes that drive HIV biology. As basic HIV research has informed the development of [...] Read more.

Since the emergence of HIV and AIDS in the early 1980s, the development of safe and effective therapies has accompanied a massive increase in our understanding of the fundamental processes that drive HIV biology. As basic HIV research has informed the development of novel therapies, HIV inhibitors have been used as probes for investigating basic mechanisms of HIV-1 replication, transmission, and pathogenesis. This positive feedback cycle has led to the development of highly effective combination antiretroviral therapy (cART), which has helped stall the progression to AIDS, prolong lives, and reduce transmission of the virus. However, to combat the growing rates of virologic failure and toxicity associated with long-term therapy, it is important to diversify our repertoire of HIV-1 treatments by identifying compounds that block additional steps not targeted by current drugs. Most of the available therapeutics disrupt early events in the replication cycle, with the exception of the protease (PR) inhibitors, which act at the virus maturation step. HIV-1 maturation consists of a series of biochemical changes that facilitate the conversion of an immature, noninfectious particle to a mature infectious virion. These changes include proteolytic processing of the Gag polyprotein by the viral protease (PR), structural rearrangement of the capsid (CA) protein, and assembly of individual CA monomers into hexamers and pentamers that ultimately form the capsid. Here, we review the development and therapeutic potential of maturation inhibitors (MIs), an experimental class of anti-HIV-1 compounds with mechanisms of action distinct from those of the PR inhibitors. We emphasize the key insights into HIV-1 biology and structure that the study of MIs has provided. We will focus on three distinct groups of inhibitors that block HIV-1 maturation: (1) compounds that block the processing of the CA-spacer peptide 1 (SP1) cleavage intermediate, the original class of compounds to which the term MI was applied; (2) CA-binding inhibitors that disrupt capsid condensation; and (3) allosteric integrase inhibitors (ALLINIs) that block the packaging of the viral RNA genome into the condensing capsid during maturation. Although these three classes of compounds have distinct structures and mechanisms of action, they share the ability to block the formation of the condensed conical capsid, thereby blocking particle infectivity. Full article

(This article belongs to the Special Issue Viruses Ten-Year Anniversary)

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32 pages, 622 KiB

Open AccessReview

Dangerous Liaisons: Gammaherpesvirus Subversion of the Immunoglobulin Repertoire

by Monika A. Zelazowska, Kevin McBride and Laurie T. Krug

Viruses 2020, 12(8), 788; https://doi.org/10.3390/v12080788 - 23 Jul 2020

Cited by 5 | Viewed by 4114

Abstract

A common biologic property of the gammaherpesviruses Epstein–Barr Virus and Kaposi sarcoma herpesvirus is their use of B lymphocytes as a reservoir of latency in healthy individuals that can undergo oncogenic transformation later in life. Gammaherpesviruses (GHVs) employ an impressive arsenal of proteins [...] Read more.

A common biologic property of the gammaherpesviruses Epstein–Barr Virus and Kaposi sarcoma herpesvirus is their use of B lymphocytes as a reservoir of latency in healthy individuals that can undergo oncogenic transformation later in life. Gammaherpesviruses (GHVs) employ an impressive arsenal of proteins and non-coding RNAs to reprogram lymphocytes for proliferative expansion. Within lymphoid tissues, the germinal center (GC) reaction is a hub of B cell proliferation and death. The goal of a GC is to generate and then select for a pool of immunoglobulin (Ig) genes that will provide a protective humoral adaptive immune response. B cells infected with GHVs are detected in GCs and bear the hallmark signatures of the mutagenic processes of somatic hypermutation and isotype class switching of the Ig genes. However, data also supports extrafollicular B cells as a reservoir engaged by GHVs. Next-generation sequencing technologies provide unprecedented detail of the Ig sequence that informs the natural history of infection at the single cell level. Here, we review recent reports from human and murine GHV systems that identify striking differences in the immunoglobulin repertoire of infected B cells compared to their uninfected counterparts. Implications for virus biology, GHV-associated cancers, and host immune dysfunction will be discussed. Full article

(This article belongs to the Special Issue Viruses Ten-Year Anniversary)

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21 pages, 1055 KiB

Open AccessReview

The Role of the Human Cytomegalovirus UL133-UL138 Gene Locus in Latency and Reactivation

by Luwanika Mlera, Melissa Moy, Kristen Maness, Linh N. Tran and Felicia D. Goodrum

Viruses 2020, 12(7), 714; https://doi.org/10.3390/v12070714 - 01 Jul 2020

Cited by 13 | Viewed by 3695

Abstract

Human cytomegalovirus (HCMV) latency, the means by which the virus persists indefinitely in an infected individual, is a major frontier of current research efforts in the field. Towards developing a comprehensive understanding of HCMV latency and its reactivation from latency, viral determinants of [...] Read more.

Human cytomegalovirus (HCMV) latency, the means by which the virus persists indefinitely in an infected individual, is a major frontier of current research efforts in the field. Towards developing a comprehensive understanding of HCMV latency and its reactivation from latency, viral determinants of latency and reactivation and their host interactions that govern the latent state and reactivation from latency have been identified. The polycistronic UL133-UL138 locus encodes determinants of both latency and reactivation. In this review, we survey the model systems used to investigate latency and new findings from these systems. Particular focus is given to the roles of the UL133, UL135, UL136 and UL138 proteins in regulating viral latency and how their known host interactions contribute to regulating host signaling pathways towards the establishment of or exit from latency. Understanding the mechanisms underlying viral latency and reactivation is important in developing strategies to block reactivation and prevent CMV disease in immunocompromised individuals, such as transplant patients. Full article

(This article belongs to the Special Issue Viruses Ten-Year Anniversary)

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27 pages, 1712 KiB

Open AccessReview

Viral Membrane Fusion and the Transmembrane Domain

by Chelsea T. Barrett and Rebecca Ellis Dutch

Viruses 2020, 12(7), 693; https://doi.org/10.3390/v12070693 - 27 Jun 2020

Cited by 35 | Viewed by 7608

Abstract

Initiation of host cell infection by an enveloped virus requires a viral-to-host cell membrane fusion event. This event is mediated by at least one viral transmembrane glycoprotein, termed the fusion protein, which is a key therapeutic target. Viral fusion proteins have been studied [...] Read more.

Initiation of host cell infection by an enveloped virus requires a viral-to-host cell membrane fusion event. This event is mediated by at least one viral transmembrane glycoprotein, termed the fusion protein, which is a key therapeutic target. Viral fusion proteins have been studied for decades, and numerous critical insights into their function have been elucidated. However, the transmembrane region remains one of the most poorly understood facets of these proteins. In the past ten years, the field has made significant advances in understanding the role of the membrane-spanning region of viral fusion proteins. We summarize developments made in the past decade that have contributed to the understanding of the transmembrane region of viral fusion proteins, highlighting not only their critical role in the membrane fusion process, but further demonstrating their involvement in several aspects of the viral lifecycle. Full article

(This article belongs to the Special Issue Viruses Ten-Year Anniversary)

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30 pages, 7771 KiB

Open AccessReview

Structural Insights into APOBEC3-Mediated Lentiviral Restriction

by Krista A. Delviks-Frankenberry, Belete A. Desimmie and Vinay K. Pathak

Viruses 2020, 12(6), 587; https://doi.org/10.3390/v12060587 - 27 May 2020

Cited by 20 | Viewed by 4041

Abstract

Mammals have developed clever adaptive and innate immune defense mechanisms to protect against invading bacterial and viral pathogens. Human innate immunity is continuously evolving to expand the repertoire of restriction factors and one such family of intrinsic restriction factors is the APOBEC3 (A3) [...] Read more.

Mammals have developed clever adaptive and innate immune defense mechanisms to protect against invading bacterial and viral pathogens. Human innate immunity is continuously evolving to expand the repertoire of restriction factors and one such family of intrinsic restriction factors is the APOBEC3 (A3) family of cytidine deaminases. The coordinated expression of seven members of the A3 family of cytidine deaminases provides intrinsic immunity against numerous foreign infectious agents and protects the host from exogenous retroviruses and endogenous retroelements. Four members of the A3 proteins—A3G, A3F, A3H, and A3D—restrict HIV-1 in the absence of virion infectivity factor (Vif); their incorporation into progeny virions is a prerequisite for cytidine deaminase-dependent and -independent activities that inhibit viral replication in the host target cell. HIV-1 encodes Vif, an accessory protein that antagonizes A3 proteins by targeting them for polyubiquitination and subsequent proteasomal degradation in the virus producing cells. In this review, we summarize our current understanding of the role of human A3 proteins as barriers against HIV-1 infection, how Vif overcomes their antiviral activity, and highlight recent structural and functional insights into A3-mediated restriction of lentiviruses. Full article

(This article belongs to the Special Issue Viruses Ten-Year Anniversary)

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15 pages, 1238 KiB

Open AccessReview

DEAD-Box Helicases: Sensors, Regulators, and Effectors for Antiviral Defense

by Frances Taschuk and Sara Cherry

Viruses 2020, 12(2), 181; https://doi.org/10.3390/v12020181 - 05 Feb 2020

Cited by 70 | Viewed by 6451

Abstract

DEAD-box helicases are a large family of conserved RNA-binding proteins that belong to the broader group of cellular DExD/H helicases. Members of the DEAD-box helicase family have roles throughout cellular RNA metabolism from biogenesis to decay. Moreover, there is emerging evidence that cellular [...] Read more.

DEAD-box helicases are a large family of conserved RNA-binding proteins that belong to the broader group of cellular DExD/H helicases. Members of the DEAD-box helicase family have roles throughout cellular RNA metabolism from biogenesis to decay. Moreover, there is emerging evidence that cellular RNA helicases, including DEAD-box helicases, play roles in the recognition of foreign nucleic acids and the modulation of viral infection. As intracellular parasites, viruses must evade detection by innate immune sensing mechanisms and degradation by cellular machinery while also manipulating host cell processes to facilitate replication. The ability of DEAD-box helicases to recognize RNA in a sequence-independent manner, as well as the breadth of cellular functions carried out by members of this family, lead them to influence innate recognition and viral infections in multiple ways. Indeed, DEAD-box helicases have been shown to contribute to intracellular immune sensing, act as antiviral effectors, and even to be coopted by viruses to promote their replication. However, our understanding of the mechanisms underlying these interactions, as well as the cellular roles of DEAD-box helicases themselves, is limited in many cases. We will discuss the diverse roles that members of the DEAD-box helicase family play during viral infections. Full article

(This article belongs to the Special Issue Viruses Ten-Year Anniversary)

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20 pages, 872 KiB

Open AccessReview

Replication Compartments of DNA Viruses in the Nucleus: Location, Location, Location

by Matthew Charman and Matthew D. Weitzman

Viruses 2020, 12(2), 151; https://doi.org/10.3390/v12020151 - 29 Jan 2020

Cited by 34 | Viewed by 6125

Abstract

DNA viruses that replicate in the nucleus encompass a range of ubiquitous and clinically important viruses, from acute pathogens to persistent tumor viruses. These viruses must co-opt nuclear processes for the benefit of the virus, whilst evading host processes that would otherwise attenuate [...] Read more.

DNA viruses that replicate in the nucleus encompass a range of ubiquitous and clinically important viruses, from acute pathogens to persistent tumor viruses. These viruses must co-opt nuclear processes for the benefit of the virus, whilst evading host processes that would otherwise attenuate viral replication. Accordingly, DNA viruses induce the formation of membraneless assemblies termed viral replication compartments (VRCs). These compartments facilitate the spatial organization of viral processes and regulate virus–host interactions. Here, we review advances in our understanding of VRCs. We cover their initiation and formation, their function as the sites of viral processes, and aspects of their composition and organization. In doing so, we highlight ongoing and emerging areas of research highly pertinent to our understanding of nuclear-replicating DNA viruses. Full article

(This article belongs to the Special Issue Viruses Ten-Year Anniversary)

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12 pages, 1261 KiB

Open AccessReview

Taking over Cellular Energy-Metabolism for TBSV Replication: The High ATP Requirement of an RNA Virus within the Viral Replication Organelle

by Peter D. Nagy and Wenwu Lin

Viruses 2020, 12(1), 56; https://doi.org/10.3390/v12010056 - 03 Jan 2020

Cited by 27 | Viewed by 5617

Abstract

Recent discoveries on virus-driven hijacking and compartmentalization of the cellular glycolytic and fermentation pathways to support robust virus replication put the spotlight on the energy requirement of viral processes. The active recruitment of glycolytic enzymes in combination with fermentation enzymes by the viral [...] Read more.

Recent discoveries on virus-driven hijacking and compartmentalization of the cellular glycolytic and fermentation pathways to support robust virus replication put the spotlight on the energy requirement of viral processes. The active recruitment of glycolytic enzymes in combination with fermentation enzymes by the viral replication proteins emphasizes the advantages of producing ATP locally within viral replication structures. This leads to a paradigm shift in our understanding of how viruses take over host metabolism to support the virus’s energy needs during the replication process. This review highlights our current understanding of how a small plant virus, Tomato bushy stunt virus, exploits a conserved energy-generating cellular pathway during viral replication. The emerging picture is that viruses not only rewire cellular metabolic pathways to obtain the necessary resources from the infected cells but the fast replicating viruses might have to actively hijack and compartmentalize the energy-producing enzymes to provide a readily available source of ATP for viral replication process. Full article

(This article belongs to the Special Issue Viruses Ten-Year Anniversary)

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47 pages, 10927 KiB

Open AccessReview

Chloroviruses

by James L. Van Etten, Irina V. Agarkova and David D. Dunigan

Viruses 2020, 12(1), 20; https://doi.org/10.3390/v12010020 - 23 Dec 2019

Cited by 45 | Viewed by 7966

Abstract

Chloroviruses are large dsDNA, plaque-forming viruses that infect certain chlorella-like green algae; the algae are normally mutualistic endosymbionts of protists and metazoans and are often referred to as zoochlorellae. The viruses are ubiquitous in inland aqueous environments throughout the world and occasionally single [...] Read more.

Chloroviruses are large dsDNA, plaque-forming viruses that infect certain chlorella-like green algae; the algae are normally mutualistic endosymbionts of protists and metazoans and are often referred to as zoochlorellae. The viruses are ubiquitous in inland aqueous environments throughout the world and occasionally single types reach titers of thousands of plaque-forming units per ml of native water. The viruses are icosahedral in shape with a spike structure located at one of the vertices. They contain an internal membrane that is required for infectivity. The viral genomes are 290 to 370 kb in size, which encode up to 16 tRNAs and 330 to ~415 proteins, including many not previously seen in viruses. Examples include genes encoding DNA restriction and modification enzymes, hyaluronan and chitin biosynthetic enzymes, polyamine biosynthetic enzymes, ion channel and transport proteins, and enzymes involved in the glycan synthesis of the virus major capsid glycoproteins. The proteins encoded by many of these viruses are often the smallest or among the smallest proteins of their class. Consequently, some of the viral proteins are the subject of intensive biochemical and structural investigation. Full article

(This article belongs to the Special Issue Viruses Ten-Year Anniversary)

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11 pages, 1066 KiB

Open AccessReview

Transmissibility versus Pathogenicity of Self-Propagating Protein Aggregates

by Byron Caughey and Allison Kraus

Viruses 2019, 11(11), 1044; https://doi.org/10.3390/v11111044 - 09 Nov 2019

Cited by 19 | Viewed by 3429

Abstract

The prion-like spreading and accumulation of specific protein aggregates appear to be central to the pathogenesis of many human diseases, including Alzheimer’s and Parkinson’s. Accumulating evidence indicates that inoculation of tissue extracts from diseased individuals into suitable experimental animals can in many cases [...] Read more.

The prion-like spreading and accumulation of specific protein aggregates appear to be central to the pathogenesis of many human diseases, including Alzheimer’s and Parkinson’s. Accumulating evidence indicates that inoculation of tissue extracts from diseased individuals into suitable experimental animals can in many cases induce the aggregation of the disease-associated protein, as well as related pathological lesions. These findings, together with the history of the prion field, have raised the questions about whether such disease-associated protein aggregates are transmissible between humans by casual or iatrogenic routes, and, if so, do they propagate enough in the new host to cause disease? These practical considerations are important because real, and perhaps even only imagined, risks of human-to-human transmission of diseases such as Alzheimer’s and Parkinson’s may force costly changes in clinical practice that, in turn, are likely to have unintended consequences. The prion field has taught us that a single protein, PrP, can aggregate into forms that can propagate exponentially in vitro, but range from being innocuous to deadly when injected into experimental animals in ways that depend strongly on factors such as conformational subtleties, routes of inoculation, and host responses. In assessing the hazards posed by various disease-associated, self-propagating protein aggregates, it is imperative to consider both their actual transmissibilities and the pathological consequences of their propagation, if any, in recipient hosts. Full article

(This article belongs to the Special Issue Viruses Ten-Year Anniversary)

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12 pages, 2757 KiB

Open AccessReview

Molecular Piracy: Redirection of Bacteriophage Capsid Assembly by Mobile Genetic Elements

by Terje Dokland

Viruses 2019, 11(11), 1003; https://doi.org/10.3390/v11111003 - 31 Oct 2019

Cited by 19 | Viewed by 5253

Abstract

Horizontal transfer of mobile genetic elements (MGEs) is a key aspect of the evolution of bacterial pathogens. Transduction by bacteriophages is especially important in this process. Bacteriophages—which assemble a machinery for efficient encapsidation and transfer of genetic material—often transfer MGEs and other chromosomal [...] Read more.

Horizontal transfer of mobile genetic elements (MGEs) is a key aspect of the evolution of bacterial pathogens. Transduction by bacteriophages is especially important in this process. Bacteriophages—which assemble a machinery for efficient encapsidation and transfer of genetic material—often transfer MGEs and other chromosomal DNA in a more-or-less nonspecific low-frequency process known as generalized transduction. However, some MGEs have evolved highly specific mechanisms to take advantage of bacteriophages for their own propagation and high-frequency transfer while strongly interfering with phage production—“molecular piracy”. These mechanisms include the ability to sense the presence of a phage entering lytic growth, specific recognition and packaging of MGE genomes into phage capsids, and the redirection of the phage assembly pathway to form capsids with a size more appropriate for the size of the MGE. This review focuses on the process of assembly redirection, which has evolved convergently in many different MGEs from across the bacterial universe. The diverse mechanisms that exist suggest that size redirection is an evolutionarily advantageous strategy for many MGEs. Full article

(This article belongs to the Special Issue Viruses Ten-Year Anniversary)

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19 pages, 1394 KiB

Open AccessReview

Evasion of Innate and Intrinsic Antiviral Pathways by the Zika Virus

by Taryn M. Serman and Michaela U. Gack

Viruses 2019, 11(10), 970; https://doi.org/10.3390/v11100970 - 22 Oct 2019

Cited by 36 | Viewed by 7662

Abstract

The Zika virus (ZIKV) is a recently emerged mosquito-borne flavivirus that, while typically asymptomatic, can cause neurological symptoms in adults and birth defects in babies born to infected mothers. The interactions of ZIKV with many different pathways in the human host ultimately determine [...] Read more.

The Zika virus (ZIKV) is a recently emerged mosquito-borne flavivirus that, while typically asymptomatic, can cause neurological symptoms in adults and birth defects in babies born to infected mothers. The interactions of ZIKV with many different pathways in the human host ultimately determine successful virus replication and ZIKV-induced pathogenesis; however, the molecular mechanisms of such host-ZIKV interactions have just begun to be elucidated. Here, we summarize the recent advances that defined the mechanisms by which ZIKV antagonizes antiviral innate immune signaling pathways, with a particular focus on evasion of the type I interferon response in the human host. Furthermore, we describe emerging evidence that indicated the contribution of several cell-intrinsic mechanisms to an effective restriction of ZIKV infection, such as nonsense-mediated mRNA decay, stress granule formation, and “reticulophagy”, a type of selective autophagy. Finally, we summarize the recent work that identified strategies by which ZIKV modulated these intrinsic antiviral responses. Full article

(This article belongs to the Special Issue Viruses Ten-Year Anniversary)

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22 pages, 1898 KiB

Open AccessReview

Persistent Infection with Herpes Simplex Virus 1 and Alzheimer’s Disease—A Call to Study How Variability in Both Virus and Host may Impact Disease

by Colleen A. Mangold and Moriah L. Szpara

Viruses 2019, 11(10), 966; https://doi.org/10.3390/v11100966 - 20 Oct 2019

Cited by 26 | Viewed by 9138

Abstract

Increasing attention has focused on the contributions of persistent microbial infections with the manifestation of disease later in life, including neurodegenerative conditions such as Alzheimer’s disease (AD). Current data has shown the presence of herpes simplex virus 1 (HSV-1) in regions of the [...] Read more.

Increasing attention has focused on the contributions of persistent microbial infections with the manifestation of disease later in life, including neurodegenerative conditions such as Alzheimer’s disease (AD). Current data has shown the presence of herpes simplex virus 1 (HSV-1) in regions of the brain that are impacted by AD in elderly individuals. Additionally, neuronal infection with HSV-1 triggers the accumulation of amyloid beta deposits and hyperphosphorylated tau, and results in oxidative stress and synaptic dysfunction. All of these factors are implicated in the development of AD. These data highlight the fact that persistent viral infection is likely a contributing factor, rather than a sole cause of disease. Details of the correlations between HSV-1 infection and AD development are still just beginning to emerge. Future research should investigate the relative impacts of virus strain- and host-specific factors on the induction of neurodegenerative processes over time, using models such as infected neurons in vitro, and animal models in vivo, to begin to understand their relationship with cognitive dysfunction. Full article

(This article belongs to the Special Issue Viruses Ten-Year Anniversary)

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9 pages, 484 KiB

Open AccessReview

Diverse Mechanisms Underlie Enhancement of Enteric Viruses by the Mammalian Intestinal Microbiota

by Alexa N. Roth, Katrina R. Grau and Stephanie M. Karst

Viruses 2019, 11(8), 760; https://doi.org/10.3390/v11080760 - 17 Aug 2019

Cited by 11 | Viewed by 5382

Abstract

Over the past two decades, there has been tremendous progress in understanding the impact of the intestinal microbiota on mammalian metabolism, physiology, and immune development and function. There has also been substantial advancement in elucidating the interplay between commensal and pathogenic bacteria. Relatively [...] Read more.

Over the past two decades, there has been tremendous progress in understanding the impact of the intestinal microbiota on mammalian metabolism, physiology, and immune development and function. There has also been substantial advancement in elucidating the interplay between commensal and pathogenic bacteria. Relatively more recently, researchers have begun to investigate the effect of the intestinal microbiota on viral pathogenesis. Indeed, a growing body of literature has reported that commensal bacteria within the mammalian intestinal tract enhance enteric virus infections through a variety of mechanisms. Commensal bacteria or bacterial glycans can increase the stability of enteric viruses, enhance virus binding to host receptors, modulate host immune responses in a proviral manner, expand the numbers of host cell targets, and facilitate viral recombination. In this review, we will summarize the current literature exploring these effects of the intestinal microbiota on enteric virus infections. Full article

(This article belongs to the Special Issue Viruses Ten-Year Anniversary)

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12 pages, 1545 KiB

Open AccessReview

Trans-Acting RNA–RNA Interactions in Segmented RNA Viruses

by Laura R. Newburn and K. Andrew White

Viruses 2019, 11(8), 751; https://doi.org/10.3390/v11080751 - 14 Aug 2019

Cited by 13 | Viewed by 12525

Abstract

RNA viruses represent a large and important group of pathogens that infect a broad range of hosts. Segmented RNA viruses are a subclass of this group that encode their genomes in two or more molecules and package all of their RNA segments in [...] Read more.

RNA viruses represent a large and important group of pathogens that infect a broad range of hosts. Segmented RNA viruses are a subclass of this group that encode their genomes in two or more molecules and package all of their RNA segments in a single virus particle. These divided genomes come in different forms, including double-stranded RNA, coding-sense single-stranded RNA, and noncoding single-stranded RNA. Genera that possess these genome types include, respectively, Orbivirus (e.g., Bluetongue virus), Dianthovirus (e.g., Red clover necrotic mosaic virus) and Alphainfluenzavirus (e.g., Influenza A virus). Despite their distinct genomic features and diverse host ranges (i.e., animals, plants, and humans, respectively) each of these viruses uses trans-acting RNA–RNA interactions (tRRIs) to facilitate co-packaging of their segmented genome. The tRRIs occur between different viral genome segments and direct the selective packaging of a complete genome complement. Here we explore the current state of understanding of tRRI-mediated co-packaging in the abovementioned viruses and examine other known and potential functions for this class of RNA–RNA interaction. Full article

(This article belongs to the Special Issue Viruses Ten-Year Anniversary)

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20 pages, 1330 KiB

Open AccessReview

Enteroviruses: A Gut-Wrenching Game of Entry, Detection, and Evasion

by Alexandra I. Wells and Carolyn B. Coyne

Viruses 2019, 11(5), 460; https://doi.org/10.3390/v11050460 - 21 May 2019

Cited by 61 | Viewed by 10520

Abstract

Enteroviruses are a major source of human disease, particularly in neonates and young children where infections can range from acute, self-limited febrile illness to meningitis, endocarditis, hepatitis, and acute flaccid myelitis. The enterovirus genus includes poliovirus, coxsackieviruses, echoviruses, enterovirus 71, and enterovirus D68. [...] Read more.

Enteroviruses are a major source of human disease, particularly in neonates and young children where infections can range from acute, self-limited febrile illness to meningitis, endocarditis, hepatitis, and acute flaccid myelitis. The enterovirus genus includes poliovirus, coxsackieviruses, echoviruses, enterovirus 71, and enterovirus D68. Enteroviruses primarily infect by the fecal–oral route and target the gastrointestinal epithelium early during their life cycles. In addition, spread via the respiratory tract is possible and some enteroviruses such as enterovirus D68 are preferentially spread via this route. Once internalized, enteroviruses are detected by intracellular proteins that recognize common viral features and trigger antiviral innate immune signaling. However, co-evolution of enteroviruses with humans has allowed them to develop strategies to evade detection or disrupt signaling. In this review, we will discuss how enteroviruses infect the gastrointestinal tract, the mechanisms by which cells detect enterovirus infections, and the strategies enteroviruses use to escape this detection. Full article

(This article belongs to the Special Issue Viruses Ten-Year Anniversary)

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25 pages, 1031 KiB

Open AccessReview

Manipulation of Epithelial Differentiation by HPV Oncoproteins

by Elizabeth A. White

Viruses 2019, 11(4), 369; https://doi.org/10.3390/v11040369 - 22 Apr 2019

Cited by 39 | Viewed by 5974

Abstract

Papillomaviruses replicate and cause disease in stratified squamous epithelia. Epithelial differentiation is essential for the progression of papillomavirus replication, but differentiation is also impaired by papillomavirus-encoded proteins. The papillomavirus E6 and E7 oncoproteins partially inhibit and/or delay epithelial differentiation and some of the [...] Read more.

Papillomaviruses replicate and cause disease in stratified squamous epithelia. Epithelial differentiation is essential for the progression of papillomavirus replication, but differentiation is also impaired by papillomavirus-encoded proteins. The papillomavirus E6 and E7 oncoproteins partially inhibit and/or delay epithelial differentiation and some of the mechanisms by which they do so are beginning to be defined. This review will outline the key features of the relationship between HPV infection and differentiation and will summarize the data indicating that papillomaviruses alter epithelial differentiation. It will describe what is known so far and will highlight open questions about the differentiation-inhibitory mechanisms employed by the papillomaviruses. Full article

(This article belongs to the Special Issue Viruses Ten-Year Anniversary)

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28 pages, 4865 KiB

Open AccessReview

Discovery and Further Studies on Giant Viruses at the IHU Mediterranee Infection That Modified the Perception of the Virosphere

by Clara Rolland, Julien Andreani, Amina Cherif Louazani, Sarah Aherfi, Rania Francis, Rodrigo Rodrigues, Ludmila Santos Silva, Dehia Sahmi, Said Mougari, Nisrine Chelkha, Meriem Bekliz, Lorena Silva, Felipe Assis, Fábio Dornas, Jacques Yaacoub Bou Khalil, Isabelle Pagnier, Christelle Desnues, Anthony Levasseur, Philippe Colson, Jônatas Abrahão and Bernard La Scola Show full author list Hide full author list

Viruses 2019, 11(4), 312; https://doi.org/10.3390/v11040312 - 30 Mar 2019

Cited by 19 | Viewed by 7057

Abstract

The history of giant viruses began in 2003 with the identification of Acanthamoeba polyphaga mimivirus. Since then, giant viruses of amoeba enlightened an unknown part of the viral world, and every discovery and characterization of a new giant virus modifies our perception of [...] Read more.

The history of giant viruses began in 2003 with the identification of Acanthamoeba polyphaga mimivirus. Since then, giant viruses of amoeba enlightened an unknown part of the viral world, and every discovery and characterization of a new giant virus modifies our perception of the virosphere. This notably includes their exceptional virion sizes from 200 nm to 2 µm and their genomic complexity with length, number of genes, and functions such as translational components never seen before. Even more surprising, Mimivirus possesses a unique mobilome composed of virophages, transpovirons, and a defense system against virophages named Mimivirus virophage resistance element (MIMIVIRE). From the discovery and isolation of new giant viruses to their possible roles in humans, this review shows the active contribution of the University Hospital Institute (IHU) Mediterranee Infection to the growing knowledge of the giant viruses’ field. Full article

(This article belongs to the Special Issue Viruses Ten-Year Anniversary)

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16 pages, 800 KiB

Open AccessReview

HIV-1 Envelope Glycoprotein at the Interface of Host Restriction and Virus Evasion

by Saina Beitari, Yimeng Wang, Shan-Lu Liu and Chen Liang

Viruses 2019, 11(4), 311; https://doi.org/10.3390/v11040311 - 30 Mar 2019

Cited by 16 | Viewed by 5576

Abstract

Without viral envelope proteins, viruses cannot enter cells to start infection. As the major viral proteins present on the surface of virions, viral envelope proteins are a prominent target of the host immune system in preventing and ultimately eliminating viral infection. In addition [...] Read more.

Without viral envelope proteins, viruses cannot enter cells to start infection. As the major viral proteins present on the surface of virions, viral envelope proteins are a prominent target of the host immune system in preventing and ultimately eliminating viral infection. In addition to the well-appreciated adaptive immunity that produces envelope protein-specific antibodies and T cell responses, recent studies have begun to unveil a rich layer of host innate immune mechanisms restricting viral entry. This review focuses on the exciting progress that has been made in this new direction of research, by discussing various known examples of host restriction of viral entry, and diverse viral countering strategies, in particular, the emerging role of viral envelope proteins in evading host innate immune suppression. We will also highlight the effective cooperation between innate and adaptive immunity to achieve the synergistic control of viral infection by targeting viral envelope protein and checking viral escape. Given that many of the related findings were made with HIV-1, we will use HIV-1 as the model virus to illustrate the basic principles and molecular mechanisms on host restriction targeting HIV-1 envelope protein. Full article

(This article belongs to the Special Issue Viruses Ten-Year Anniversary)

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17 pages, 1741 KiB

Open AccessReview

IFN Signaling in Inflammation and Viral Infections: New Insights from Fish Models

by Christelle Langevin, Pierre Boudinot and Bertrand Collet

Viruses 2019, 11(3), 302; https://doi.org/10.3390/v11030302 - 26 Mar 2019

Cited by 26 | Viewed by 4789

Abstract

The overarching structure of the type I interferon (IFN) system is conserved across vertebrates. However, the variable numbers of whole genome duplication events during fish evolution offer opportunities for the expansion, diversification, and new functionalization of the genes that are involved in antiviral [...] Read more.

The overarching structure of the type I interferon (IFN) system is conserved across vertebrates. However, the variable numbers of whole genome duplication events during fish evolution offer opportunities for the expansion, diversification, and new functionalization of the genes that are involved in antiviral immunity. In this review, we examine how fish models provide new insights about the implication of virus-driven inflammation in immunity and hematopoiesis. Mechanisms that have been discovered in fish, such as the strong adjuvant effect of type I IFN that is used with DNA vaccination, constitute good models to understand how virus-induced inflammatory mechanisms can interfere with adaptive responses. We also comment on new discoveries regarding the role of pathogen-induced inflammation in the development and guidance of hematopoietic stem cells in zebrafish. These findings raise issues about the potential interferences of viral infections with the establishment of the immune system. Finally, the recent development of genome editing provides new opportunities to dissect the roles of the key players involved in the antiviral response in fish, hence enhancing the power of comparative approaches. Full article

(This article belongs to the Special Issue Viruses Ten-Year Anniversary)

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16 pages, 3482 KiB

Open AccessReview

Function, Architecture, and Biogenesis of Reovirus Replication Neoorganelles

by Raquel Tenorio, Isabel Fernández de Castro, Jonathan J. Knowlton, Paula F. Zamora, Danica M. Sutherland, Cristina Risco and Terence S. Dermody

Viruses 2019, 11(3), 288; https://doi.org/10.3390/v11030288 - 21 Mar 2019

Cited by 27 | Viewed by 10945

Abstract

Most viruses that replicate in the cytoplasm of host cells form neoorganelles that serve as sites of viral genome replication and particle assembly. These highly specialized structures concentrate viral proteins and nucleic acids, prevent the activation of cell-intrinsic defenses, and coordinate the release [...] Read more.

Most viruses that replicate in the cytoplasm of host cells form neoorganelles that serve as sites of viral genome replication and particle assembly. These highly specialized structures concentrate viral proteins and nucleic acids, prevent the activation of cell-intrinsic defenses, and coordinate the release of progeny particles. Reoviruses are common pathogens of mammals that have been linked to celiac disease and show promise for oncolytic applications. These viruses form nonenveloped, double-shelled virions that contain ten segments of double-stranded RNA. Replication organelles in reovirus-infected cells are nucleated by viral nonstructural proteins µNS and σNS. Both proteins partition the endoplasmic reticulum to form the matrix of these structures. The resultant membranous webs likely serve to anchor viral RNA–protein complexes for the replication of the reovirus genome and the assembly of progeny virions. Ongoing studies of reovirus replication organelles will advance our knowledge about the strategies used by viruses to commandeer host biosynthetic pathways and may expose new targets for therapeutic intervention against diverse families of pathogenic viruses. Full article

(This article belongs to the Special Issue Viruses Ten-Year Anniversary)

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23 pages, 2418 KiB

Open AccessReview

Packaging of Genomic RNA in Positive-Sense Single-Stranded RNA Viruses: A Complex Story

by Mauricio Comas-Garcia

Viruses 2019, 11(3), 253; https://doi.org/10.3390/v11030253 - 13 Mar 2019

Cited by 34 | Viewed by 9650

Abstract

The packaging of genomic RNA in positive-sense single-stranded RNA viruses is a key part of the viral infectious cycle, yet this step is not fully understood. Unlike double-stranded DNA and RNA viruses, this process is coupled with nucleocapsid assembly. The specificity of RNA [...] Read more.

The packaging of genomic RNA in positive-sense single-stranded RNA viruses is a key part of the viral infectious cycle, yet this step is not fully understood. Unlike double-stranded DNA and RNA viruses, this process is coupled with nucleocapsid assembly. The specificity of RNA packaging depends on multiple factors: (i) one or more packaging signals, (ii) RNA replication, (iii) translation, (iv) viral factories, and (v) the physical properties of the RNA. The relative contribution of each of these factors to packaging specificity is different for every virus. In vitro and in vivo data show that there are different packaging mechanisms that control selective packaging of the genomic RNA during nucleocapsid assembly. The goals of this article are to explain some of the key experiments that support the contribution of these factors to packaging selectivity and to draw a general scenario that could help us move towards a better understanding of this step of the viral infectious cycle. Full article

(This article belongs to the Special Issue Viruses Ten-Year Anniversary)

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