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Special Issue "Breakthroughs in Viral Replication"

A special issue of Viruses (ISSN 1999-4915).

Deadline for manuscript submissions: closed (30 November 2018)

Special Issue Editors

Guest Editor
Dr. Eric O. Freed

Director, HIV Dynamics and Replication Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702-1201, USA
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Phone: 301-846-6223
Guest Editor
Dr. Albert Bosch

Enteric Virus Laboratory, School of Biology, University of Barcelona, Spain
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Special Issue Information

Dear Colleagues,

This Special Issue is related to the conference "Viruses 2018–Breakthroughs in Viral Replication" which will be held at the University of Barcelona, Barcelona, Spain, 7–9 February, 2018.

Viral infections continue to cause substantial morbidity and mortality in humans and all other living organisms. Wave upon wave of viral pandemics are having a major impact on global health. At the same time, great strides are being made in understanding at the molecular, cellular, organismal and epidemiological level how viruses replicate and induce pathology. This increase in knowledge is being translated into new treatments and vaccines for many viral infections.

Symposium participants, as well as all researchers working in the field, are cordially invited to contribute original research papers or reviews to this Special Issue of Viruses, which will focus on the progress being made in understanding virus replication, structure, transmission, pathogenesis, and antiviral immunity.

Dr. Eric O. Freed
Dr. Albert Bosch
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Viruses is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 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.

Published Papers (10 papers)

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Research

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Open AccessArticle Antiviral RNA Interference Activity in Cells of the Predatory Mosquito, Toxorhynchites amboinensis
Viruses 2018, 10(12), 694; https://doi.org/10.3390/v10120694
Received: 10 October 2018 / Revised: 19 November 2018 / Accepted: 4 December 2018 / Published: 6 December 2018
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Abstract
Arthropod vectors control the replication of arboviruses through their innate antiviral immune responses. In particular, the RNA interference (RNAi) pathways are of notable significance for the control of viral infections. Although much has been done to understand the role of RNAi in vector
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Arthropod vectors control the replication of arboviruses through their innate antiviral immune responses. In particular, the RNA interference (RNAi) pathways are of notable significance for the control of viral infections. Although much has been done to understand the role of RNAi in vector populations, little is known about its importance in non-vector mosquito species. In this study, we investigated the presence of an RNAi response in Toxorhynchites amboinensis, which is a non-blood feeding species proposed as a biological control agent against pest mosquitoes. Using a derived cell line (TRA-171), we demonstrate that these mosquitoes possess a functional RNAi response that is active against a mosquito-borne alphavirus, Semliki Forest virus. As observed in vector mosquito species, small RNAs are produced that target viral sequences. The size and characteristics of these small RNAs indicate that both the siRNA and piRNA pathways are induced in response to infection. Taken together, this data suggests that Tx. amboinensis are able to control viral infections in a similar way to natural arbovirus vector mosquito species. Understanding their ability to manage arboviral infections will be advantageous when assessing these and similar species as biological control agents. Full article
(This article belongs to the Special Issue Breakthroughs in Viral Replication)
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Open AccessArticle Evidence of Human Parvovirus B19 Infection in the Post-Mortem Brain Tissue of the Elderly
Viruses 2018, 10(11), 582; https://doi.org/10.3390/v10110582
Received: 22 September 2018 / Revised: 23 October 2018 / Accepted: 24 October 2018 / Published: 25 October 2018
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Abstract
After primary exposure, the human parvovirus B19 (B19V) genome may remain in the central nervous system (CNS), establishing a lifelong latency. The structural characteristics and functions of the infected cells are essential for the virus to complete its life cycle. Although B19V has
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After primary exposure, the human parvovirus B19 (B19V) genome may remain in the central nervous system (CNS), establishing a lifelong latency. The structural characteristics and functions of the infected cells are essential for the virus to complete its life cycle. Although B19V has been detected in the brain tissue by sequencing PCR products, little is known about its in vivo cell tropism and pathogenic potential in the CNS. To detect B19V and investigate the distribution of its target cells in the CNS, we studied brain autopsies of elderly subjects using molecular virology, and optical and electron microscopy methods. Our study detected B19V in brain tissue samples from both encephalopathy and control groups, suggesting virus persistence within the CNS throughout the host’s lifetime. It appears that within the CNS, the main target of B19V is oligodendrocytes. The greatest number of B19V-positive oligodendrocytes was found in the white matter of the frontal lobe. The number was significantly lower in the gray matter of the frontal lobe (p = 0.008) and the gray and white matter of the temporal lobes (p < 0.0001). The morphological changes observed in the encephalopathy group, propose a possible B19V involvement in the demyelination process. Full article
(This article belongs to the Special Issue Breakthroughs in Viral Replication)
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Open AccessArticle Rubella Virus Strain-Associated Differences in the Induction of Oxidative Stress Are Independent of Their Interferon Activation
Viruses 2018, 10(10), 540; https://doi.org/10.3390/v10100540
Received: 17 August 2018 / Revised: 26 September 2018 / Accepted: 28 September 2018 / Published: 3 October 2018
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Abstract
Rubella virus (RV) infection impacts cellular metabolic activity in a complex manner with strain-specific nutritional requirements. Here we addressed whether this differential metabolic influence was associated with differences in oxidative stress induction and subsequently with innate immune response activation. The low passaged clinical
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Rubella virus (RV) infection impacts cellular metabolic activity in a complex manner with strain-specific nutritional requirements. Here we addressed whether this differential metabolic influence was associated with differences in oxidative stress induction and subsequently with innate immune response activation. The low passaged clinical isolates of RV examined in this study induced oxidative stress as validated through generation of the reactive oxygen species (ROS) cytoplasmic hydrogen peroxide and mitochondrial superoxide. The addition of the cytoplasmic and mitochondrial ROS scavengers N-acetyl-l-cysteine and MitoTEMPO, respectively, reduced RV-associated cytopathogenicity and caspase activation. While the degree of oxidative stress induction varied among RV clinical isolates, the level of innate immune response and interferon-stimulated gene activation was comparable. The type III IFNs were highly upregulated in all cell culture systems tested. However, only pre-stimulation with IFN β slightly reduced RV replication indicating that RV appears to have evolved the ability to counteract innate immune response mechanisms. Through the data presented, we showed that the ability of RV to induce oxidative stress was independent of its capacity to stimulate and counteract the intrinsic innate immune response. Full article
(This article belongs to the Special Issue Breakthroughs in Viral Replication)
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Open AccessArticle The Inhibition of HIV-1 Entry Imposed by Interferon Inducible Transmembrane Proteins Is Independent of Co-Receptor Usage
Viruses 2018, 10(8), 413; https://doi.org/10.3390/v10080413
Received: 24 June 2018 / Revised: 3 August 2018 / Accepted: 4 August 2018 / Published: 7 August 2018
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Abstract
Interferon inducible transmembrane proteins (IFITMs) are one of several IFN-stimulated genes (ISGs) that restrict entry of enveloped viruses, including flaviviruses, filoviruses and retroviruses. It has been recently reported that in U87 glioblastoma cells IFITM proteins inhibit HIV-1 entry in a co-receptor-dependent manner, that
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Interferon inducible transmembrane proteins (IFITMs) are one of several IFN-stimulated genes (ISGs) that restrict entry of enveloped viruses, including flaviviruses, filoviruses and retroviruses. It has been recently reported that in U87 glioblastoma cells IFITM proteins inhibit HIV-1 entry in a co-receptor-dependent manner, that is, IFITM1 is more inhibitory on CCR5 tropic HIV-1 whereas IFITM2/3 confers a greater suppression of CXCR4 counterparts. However, how entry of HIV-1 with distinct co-receptor usage is modulated by different IFITM orthologs in physiologically relevant CD4+ T cells and monocytes/macrophages has not been investigated in detail. Here, we report that overexpression of IFITM1, 2 and 3 in human CD4+ HuT78 cells, SupT1 cells, monocytic THP-1 cells and U87 cells expressing CD4 and co-receptor CCR5 or CXCR4, suppressed entry of CXCR4 tropic viruses NL4.3 and HXB2, CCR5 tropic viruses AD8 and JRFL, dual tropic 89.6 virus, as well as a panel of 32 transmitted founder (T/F) viruses, with a consistent order of potency, that is, IFITM3 > IFITM2 > IFITM1. Consistent with previous reports, we found that some CCR5-using HIV-1 isolates, such as AD8 and JRFL, were relatively resistant to inhibition by IFITM2 and IFITM3, although the effect can be cell-type dependent. However, in no case have we observed that IFITM1 had a stronger inhibition on entry of any HIV-1 strains tested, including those of CCR5-using T/Fs. We knocked down the endogenous IFITMs in peripheral blood mononuclear cells (PBMCs) and purified CD4+ T cells and observed that, while this treatment did greatly enhance the multiple-round of HIV-1 replication but had modest effect to rescue the single-round HIV-1 infection, reinforcing our previous conclusion that the predominant effect of IFITMs on HIV-1 infection is in viral producer cells, rather than in target cells to block viral entry. Overall, our results argue against the idea that IFITM proteins distinguish co-receptors CCR5 and CXCR4 to inhibit entry but emphasize that the predominant role of IFITMs on HIV-1 is in producer cells that intrinsically impair the viral infectivity. Full article
(This article belongs to the Special Issue Breakthroughs in Viral Replication)
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Open AccessArticle Analyses of Tissue Culture Adaptation of Human Herpesvirus-6A by Whole Genome Deep Sequencing Redefines the Reference Sequence and Identifies Virus Entry Complex Changes
Viruses 2018, 10(1), 16; https://doi.org/10.3390/v10010016
Received: 30 November 2017 / Revised: 23 December 2017 / Accepted: 26 December 2017 / Published: 31 December 2017
Cited by 1 | PDF Full-text (1338 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Tissue-culture adaptation of viruses can modulate infection. Laboratory passage and bacterial artificial chromosome (BAC)mid cloning of human cytomegalovirus, HCMV, resulted in genomic deletions and rearrangements altering genes encoding the virus entry complex, which affected cellular tropism, virulence, and vaccine development. Here, we analyse
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Tissue-culture adaptation of viruses can modulate infection. Laboratory passage and bacterial artificial chromosome (BAC)mid cloning of human cytomegalovirus, HCMV, resulted in genomic deletions and rearrangements altering genes encoding the virus entry complex, which affected cellular tropism, virulence, and vaccine development. Here, we analyse these effects on the reference genome for related betaherpesviruses, Roseolovirus, human herpesvirus 6A (HHV-6A) strain U1102. This virus is also naturally “cloned” by germline subtelomeric chromosomal-integration in approximately 1% of human populations, and accurate references are key to understanding pathological relationships between exogenous and endogenous virus. Using whole genome next-generation deep-sequencing Illumina-based methods, we compared the original isolate to tissue-culture passaged and the BACmid-cloned virus. This re-defined the reference genome showing 32 corrections and 5 polymorphisms. Furthermore, minor variant analyses of passaged and BACmid virus identified emerging populations of a further 32 single nucleotide polymorphisms (SNPs) in 10 loci, half non-synonymous indicating cell-culture selection. Analyses of the BAC-virus genome showed deletion of the BAC cassette via loxP recombination removing green fluorescent protein (GFP)-based selection. As shown for HCMV culture effects, select HHV-6A SNPs mapped to genes encoding mediators of virus cellular entry, including virus envelope glycoprotein genes gB and the gH/gL complex. Comparative models suggest stabilisation of the post-fusion conformation. These SNPs are essential to consider in vaccine-design, antimicrobial-resistance, and pathogenesis. Full article
(This article belongs to the Special Issue Breakthroughs in Viral Replication)
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Review

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Open AccessReview Monitoring HIV-1 Assembly in Living Cells: Insights from Dynamic and Single Molecule Microscopy
Viruses 2019, 11(1), 72; https://doi.org/10.3390/v11010072
Received: 6 November 2018 / Revised: 31 December 2018 / Accepted: 12 January 2019 / Published: 16 January 2019
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Abstract
The HIV-1 assembly process is a multi-complex mechanism that takes place at the host cell plasma membrane. It requires a spatio-temporal coordination of events to end up with a full mature and infectious virus. The molecular mechanisms of HIV-1 assembly have been extensively
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The HIV-1 assembly process is a multi-complex mechanism that takes place at the host cell plasma membrane. It requires a spatio-temporal coordination of events to end up with a full mature and infectious virus. The molecular mechanisms of HIV-1 assembly have been extensively studied during the past decades, in order to dissect the respective roles of the structural and non-structural viral proteins of the viral RNA genome and of some host cell factors. Nevertheless, the time course of HIV-1 assembly was observed in living cells only a decade ago. The very recent revolution of optical microscopy, combining high speed and high spatial resolution, in addition to improved fluorescent tags for proteins, now permits study of HIV-1 assembly at the single molecule level within living cells. In this review, after a short description of these new approaches, we will discuss how HIV-1 assembly at the cell plasma membrane has been revisited using advanced super resolution microscopy techniques and how it can bridge the study of viral assembly from the single molecule to the entire host cell. Full article
(This article belongs to the Special Issue Breakthroughs in Viral Replication)
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Open AccessReview Chaperoning the Mononegavirales: Current Knowledge and Future Directions
Viruses 2018, 10(12), 699; https://doi.org/10.3390/v10120699
Received: 16 November 2018 / Revised: 4 December 2018 / Accepted: 5 December 2018 / Published: 8 December 2018
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Abstract
The order Mononegavirales harbors numerous viruses of significant relevance to human health, including both established and emerging infections. Currently, vaccines are only available for a small subset of these viruses, and antiviral therapies remain limited. Being obligate cellular parasites, viruses must utilize the
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The order Mononegavirales harbors numerous viruses of significant relevance to human health, including both established and emerging infections. Currently, vaccines are only available for a small subset of these viruses, and antiviral therapies remain limited. Being obligate cellular parasites, viruses must utilize the cellular machinery for their replication and spread. Therefore, targeting cellular pathways used by viruses can provide novel therapeutic approaches. One of the key challenges confronted by both hosts and viruses alike is the successful folding and maturation of proteins. In cells, this task is faced by cellular molecular chaperones, a group of conserved and abundant proteins that oversee protein folding and help maintain protein homeostasis. In this review, we summarize the current knowledge of how the Mononegavirales interact with cellular chaperones, highlight key gaps in our knowledge, and discuss the potential of chaperone inhibitors as antivirals. Full article
(This article belongs to the Special Issue Breakthroughs in Viral Replication)
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Open AccessReview IP6 Regulation of HIV Capsid Assembly, Stability, and Uncoating
Viruses 2018, 10(11), 640; https://doi.org/10.3390/v10110640
Received: 17 October 2018 / Revised: 12 November 2018 / Accepted: 13 November 2018 / Published: 15 November 2018
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Abstract
The mechanisms that drive formation of the HIV capsid, first as an immature particle and then as a mature protein shell, remain incompletely understood. Recent discoveries of positively-charged rings in the immature and mature protein hexamer subunits that comprise them and their binding
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The mechanisms that drive formation of the HIV capsid, first as an immature particle and then as a mature protein shell, remain incompletely understood. Recent discoveries of positively-charged rings in the immature and mature protein hexamer subunits that comprise them and their binding to the cellular metabolite inositol hexakisphosphate (IP6) have stimulated exciting new hypotheses. In this paper, we discuss how data from multiple structural and biochemical approaches are revealing potential roles for IP6 in the HIV-1 replication cycle from assembly to uncoating. Full article
(This article belongs to the Special Issue Breakthroughs in Viral Replication)
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Open AccessReview ISG15, a Small Molecule with Huge Implications: Regulation of Mitochondrial Homeostasis
Viruses 2018, 10(11), 629; https://doi.org/10.3390/v10110629
Received: 26 October 2018 / Revised: 8 November 2018 / Accepted: 9 November 2018 / Published: 13 November 2018
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Abstract
Viruses are responsible for the majority of infectious diseases, from the common cold to HIV/AIDS or hemorrhagic fevers, the latter with devastating effects on the human population. Accordingly, the development of efficient antiviral therapies is a major goal and a challenge for the
[...] Read more.
Viruses are responsible for the majority of infectious diseases, from the common cold to HIV/AIDS or hemorrhagic fevers, the latter with devastating effects on the human population. Accordingly, the development of efficient antiviral therapies is a major goal and a challenge for the scientific community, as we are still far from understanding the molecular mechanisms that operate after virus infection. Interferon-stimulated gene 15 (ISG15) plays an important antiviral role during viral infection. ISG15 catalyzes a ubiquitin-like post-translational modification termed ISGylation, involving the conjugation of ISG15 molecules to de novo synthesized viral or cellular proteins, which regulates their stability and function. Numerous biomedically relevant viruses are targets of ISG15, as well as proteins involved in antiviral immunity. Beyond their role as cellular powerhouses, mitochondria are multifunctional organelles that act as signaling hubs in antiviral responses. In this review, we give an overview of the biological consequences of ISGylation for virus infection and host defense. We also compare several published proteomic studies to identify and classify potential mitochondrial ISGylation targets. Finally, based on our recent observations, we discuss the essential functions of mitochondria in the antiviral response and examine the role of ISG15 in the regulation of mitochondrial processes, specifically OXPHOS and mitophagy. Full article
(This article belongs to the Special Issue Breakthroughs in Viral Replication)
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Open AccessReview Animal Models of Zika Virus Infection during Pregnancy
Viruses 2018, 10(11), 598; https://doi.org/10.3390/v10110598
Received: 12 October 2018 / Revised: 28 October 2018 / Accepted: 30 October 2018 / Published: 31 October 2018
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Abstract
Zika virus (ZIKV) emerged suddenly in the Americas in 2015 and was associated with a widespread outbreak of microcephaly and other severe congenital abnormalities in infants born to mothers infected during pregnancy. Vertical transmission of ZIKV in humans was confirmed when viral RNA
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Zika virus (ZIKV) emerged suddenly in the Americas in 2015 and was associated with a widespread outbreak of microcephaly and other severe congenital abnormalities in infants born to mothers infected during pregnancy. Vertical transmission of ZIKV in humans was confirmed when viral RNA was detected in fetal and placental tissues, and this outcome has been recapitulated experimentally in animals. Unlike other flaviviruses, ZIKV is both arthropod- and sexually-transmitted, and has a broad tissue tropism in humans, including multiple tissues of the reproductive tract. The threats posed by ZIKV have prompted the development of multiple in vivo models to better understand the pathogenesis of ZIKV, particularly during pregnancy. Here, we review the progress on animal models of ZIKV infection during pregnancy. These studies have generated a foundation of insights into the biology of ZIKV, and provide a means for evaluating vaccines and therapeutics. Full article
(This article belongs to the Special Issue Breakthroughs in Viral Replication)
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