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Viruses
Volume 10
Issue 1
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Viruses, Volume 10, Issue 1 (January 2018) – 50 articles

Cover Story (view full-size image): The bufavirus structures are the first determined for human-infecting members of the Protoparvovirus genus of the Parvoviridae which until recently contained only animal-infecting members. These novel human viruses bridge the structural landscape between their animal-infecting counterparts and other human-infecting parvoviruses. Their structures highlight the need to maintain surface topologies required for host-specific functions. View Paper here.
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27 pages, 2127 KiB  
Review
CRISPR/Cas9—Advancing Orthopoxvirus Genome Editing for Vaccine and Vector Development
by Arinze Okoli, Malachy I. Okeke, Morten Tryland and Ugo Moens
Viruses 2018, 10(1), 50; https://doi.org/10.3390/v10010050 - 22 Jan 2018
Cited by 27 | Viewed by 12609
Abstract
The clustered regularly interspaced short palindromic repeat (CRISPR)/associated protein 9 (Cas9) technology is revolutionizing genome editing approaches. Its high efficiency, specificity, versatility, flexibility, simplicity and low cost have made the CRISPR/Cas9 system preferable to other guided site-specific nuclease-based systems such as TALENs (Transcription [...] Read more.
The clustered regularly interspaced short palindromic repeat (CRISPR)/associated protein 9 (Cas9) technology is revolutionizing genome editing approaches. Its high efficiency, specificity, versatility, flexibility, simplicity and low cost have made the CRISPR/Cas9 system preferable to other guided site-specific nuclease-based systems such as TALENs (Transcription Activator-like Effector Nucleases) and ZFNs (Zinc Finger Nucleases) in genome editing of viruses. CRISPR/Cas9 is presently being applied in constructing viral mutants, preventing virus infections, eradicating proviral DNA, and inhibiting viral replication in infected cells. The successful adaptation of CRISPR/Cas9 to editing the genome of Vaccinia virus paves the way for its application in editing other vaccine/vector-relevant orthopoxvirus (OPXV) strains. Thus, CRISPR/Cas9 can be used to resolve some of the major hindrances to the development of OPXV-based recombinant vaccines and vectors, including sub-optimal immunogenicity; transgene and genome instability; reversion of attenuation; potential of spread of transgenes to wildtype strains and close contacts, which are important biosafety and risk assessment considerations. In this article, we review the published literature on the application of CRISPR/Cas9 in virus genome editing and discuss the potentials of CRISPR/Cas9 in advancing OPXV-based recombinant vaccines and vectors. We also discuss the application of CRISPR/Cas9 in combating viruses of clinical relevance, the limitations of CRISPR/Cas9 and the current strategies to overcome them. Full article
(This article belongs to the Special Issue Applications of CRISPR Technology in Virology 2018)
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16 pages, 10871 KiB  
Article
Zika Virus Fatally Infects Wild Type Neonatal Mice and Replicates in Central Nervous System
by Shuxuan Li, Najealicka Armstrong, Huan Zhao, Wangheng Hou, Jian Liu, Chunye Chen, Junkai Wan, Wei Wang, Chunlian Zhong, Che Liu, Hua Zhu, Ningshao Xia, Tong Cheng and Qiyi Tang
Viruses 2018, 10(1), 49; https://doi.org/10.3390/v10010049 - 22 Jan 2018
Cited by 40 | Viewed by 6110
Abstract
Zika virus (ZIKV) has been defined as a teratogenic pathogen behind the increased number of cases of microcephaly in French Polynesia, Brazil, Puerto Rico, and other South American countries. Experimental studies using animal models have achieved tremendous insight into understanding the viral pathogenesis, [...] Read more.
Zika virus (ZIKV) has been defined as a teratogenic pathogen behind the increased number of cases of microcephaly in French Polynesia, Brazil, Puerto Rico, and other South American countries. Experimental studies using animal models have achieved tremendous insight into understanding the viral pathogenesis, transmission, teratogenic mechanisms, and virus–host interactions. However, the animals used in published investigations are mostly interferon (IFN)-compromised, either genetically or via antibody treatment. Herein, we studied ZIKV infection in IFN-competent mice using African (MR766) and Asian strains (PRVABC59 and SZ-WIV01). After testing four different species of mice, we found that BALB/c neonatal mice were resistant to ZIKV infection, that Kunming, ICR and C57BL/6 neonatal mice were fatally susceptible to ZIKV infection, and that the fatality of C57BL/6 neonates from 1 to 3 days old were in a viral dose-dependent manner. The size and weight of the brain were significantly reduced, and the ZIKV-infected mice showed neuronal symptoms such as hind-limb paralysis, tremor, and poor balance during walking. Pathologic and immunofluorescent experiments revealed that ZIKV infected different areas of the central nervous system (CNS) including gray matter, hippocampus, cerebral cortex, and spinal cord, but not olfactory bulb. Interestingly, ZIKV replicated in multiple organs and resulted in pathogenesis in liver and testis, implying that ZIKV infection may engender a high health risk in neonates by postnatal infection. In summary, we investigated ZIKV pathogenesis using an animal model that is not IFN-compromised. Full article
(This article belongs to the Section Animal Viruses)
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24 pages, 1256 KiB  
Review
Verdinexor Targeting of CRM1 is a Promising Therapeutic Approach against RSV and Influenza Viruses
by Jennifer A. Pickens and Ralph A. Tripp
Viruses 2018, 10(1), 48; https://doi.org/10.3390/v10010048 - 21 Jan 2018
Cited by 23 | Viewed by 8706
Abstract
Two primary causes of respiratory tract infections are respiratory syncytial virus (RSV) and influenza viruses, both of which remain major public health concerns. There are a limited number of antiviral drugs available for the treatment of RSV and influenza, each having limited effectiveness [...] Read more.
Two primary causes of respiratory tract infections are respiratory syncytial virus (RSV) and influenza viruses, both of which remain major public health concerns. There are a limited number of antiviral drugs available for the treatment of RSV and influenza, each having limited effectiveness and each driving selective pressure for the emergence of drug-resistant viruses. Novel broad-spectrum antivirals are needed to circumvent problems with current disease intervention strategies, while improving the cytokine-induced immunopathology associated with RSV and influenza infections. In this review, we examine the use of Verdinexor (KPT-335, a novel orally bioavailable drug that functions as a selective inhibitor of nuclear export, SINE), as an antiviral with multifaceted therapeutic potential. KPT-335 works to (1) block CRM1 (i.e., Chromosome Region Maintenance 1; exportin 1 or XPO1) mediated export of viral proteins critical for RSV and influenza pathogenesis; and (2) repress nuclear factor κB (NF-κB) activation, thus reducing cytokine production and eliminating virus-associated immunopathology. The repurposing of SINE compounds as antivirals shows promise not only against RSV and influenza virus but also against other viruses that exploit the nucleus as part of their viral life cycle. Full article
(This article belongs to the Special Issue Viruses and Inflammation)
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15 pages, 344 KiB  
Review
Risk of Human Papillomavirus Infection in Cancer-Prone Individuals: What We Know
by Ruby Khoury, Sharon Sauter, Melinda Butsch Kovacic, Adam S. Nelson, Kasiani C. Myers, Parinda A. Mehta, Stella M. Davies and Susanne I. Wells
Viruses 2018, 10(1), 47; https://doi.org/10.3390/v10010047 - 20 Jan 2018
Cited by 16 | Viewed by 6072
Abstract
Human papillomavirus (HPV) infections cause a significant proportion of cancers worldwide, predominantly squamous cell carcinomas (SCC) of the mucosas and skin. High-risk HPV types are associated with SCCs of the anogenital and oropharyngeal tract. HPV oncogene activities and the biology of SCCs have [...] Read more.
Human papillomavirus (HPV) infections cause a significant proportion of cancers worldwide, predominantly squamous cell carcinomas (SCC) of the mucosas and skin. High-risk HPV types are associated with SCCs of the anogenital and oropharyngeal tract. HPV oncogene activities and the biology of SCCs have been intensely studied in laboratory models and humans. What remains largely unknown are host tissue and immune-related factors that determine an individual’s susceptibility to infection and/or carcinogenesis. Such susceptibility factors could serve to identify those at greatest risk and spark individually tailored HPV and SCC prevention efforts. Fanconi anemia (FA) is an inherited DNA repair disorder that is in part characterized by extreme susceptibility to SCCs. An increased prevalence of HPV has been reported in affected individuals, and molecular and functional connections between FA, SCC, and HPV were established in laboratory models. However, the presence of HPV in some human FA tumors is controversial, and the extent of the etiological connections remains to be established. Herein, we discuss cellular, immunological, and phenotypic features of FA, placed into the context of HPV pathogenesis. The goal is to highlight this orphan disease as a unique model system to uncover host genetic and molecular HPV features, as well as SCC susceptibility factors. Full article
(This article belongs to the Special Issue Expert Views on HPV Infection)
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23 pages, 2072 KiB  
Review
Distinct Effects of Type I and III Interferons on Enteric Viruses
by Harshad Ingle, Stefan T. Peterson and Megan T. Baldridge
Viruses 2018, 10(1), 46; https://doi.org/10.3390/v10010046 - 20 Jan 2018
Cited by 47 | Viewed by 7893
Abstract
Interferons (IFNs) are key host cytokines in the innate immune response to viral infection, and recent work has identified unique roles for IFN subtypes in regulating different aspects of infection. Currently emerging is a common theme that type III IFNs are critical in [...] Read more.
Interferons (IFNs) are key host cytokines in the innate immune response to viral infection, and recent work has identified unique roles for IFN subtypes in regulating different aspects of infection. Currently emerging is a common theme that type III IFNs are critical in localized control of infection at mucosal barrier sites, while type I IFNs are important for broad systemic control of infections. The intestine is a particular site of interest for exploring these effects, as in addition to being the port of entry for a multitude of pathogens, it is a complex tissue with a variety of cell types as well as the presence of the intestinal microbiota. Here we focus on the roles of type I and III IFNs in control of enteric viruses, discussing what is known about signaling downstream from these cytokines, including induction of specific IFN-stimulated genes. We review viral strategies to evade IFN responses, effects of IFNs on the intestine, interactions between IFNs and the microbiota, and briefly discuss the role of IFNs in controlling viral infections at other barrier sites. Enhanced understanding of the coordinate roles of IFNs in control of viral infections may facilitate development of antiviral therapeutic strategies; here we highlight potential avenues for future exploration. Full article
(This article belongs to the Special Issue Viruses–Bacteria Interactions in the Gut)
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20 pages, 1937 KiB  
Review
The Role of E6 Spliced Isoforms (E6*) in Human Papillomavirus-Induced Carcinogenesis
by Leslie Olmedo-Nieva, J. Omar Muñoz-Bello, Adriana Contreras-Paredes and Marcela Lizano
Viruses 2018, 10(1), 45; https://doi.org/10.3390/v10010045 - 18 Jan 2018
Cited by 52 | Viewed by 8154
Abstract
Persistent infections with High Risk Human Papillomaviruses (HR-HPVs) are the main cause of cervical cancer development. The E6 and E7 oncoproteins of HR-HPVs are derived from a polycistronic pre-mRNA transcribed from an HPV early promoter. Through alternative splicing, this pre-mRNA produces a variety [...] Read more.
Persistent infections with High Risk Human Papillomaviruses (HR-HPVs) are the main cause of cervical cancer development. The E6 and E7 oncoproteins of HR-HPVs are derived from a polycistronic pre-mRNA transcribed from an HPV early promoter. Through alternative splicing, this pre-mRNA produces a variety of E6 spliced transcripts termed E6*. In pre-malignant lesions and HPV-related cancers, different E6/E6* transcriptional patterns have been found, although they have not been clearly associated to cancer development. Moreover, there is a controversy about the participation of E6* proteins in cancer progression. This review addresses the regulation of E6 splicing and the different functions that have been found for E6* proteins, as well as their possible role in HPV-induced carcinogenesis. Full article
(This article belongs to the Section Animal Viruses)
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7 pages, 3606 KiB  
Case Report
Viral and Antibody Kinetics, and Mosquito Infectivity of an Imported Case of Zika Fever Due to Asian Genotype (American Strain) in Singapore
by Cheong Huat Tan, Li Kiang Tan, Hapuarachchige Chanditha Hapuarachchi, Yee Ling Lai, Pei Sze Jeslyn Wong, Grace Yap, Keng Wai Mak, Wing Yan Wong, Yee Sin Leo, Mei Chun Wong and Lee Ching Ng
Viruses 2018, 10(1), 44; https://doi.org/10.3390/v10010044 - 18 Jan 2018
Cited by 10 | Viewed by 4404
Abstract
We report a case of a Singaporean who acquired Zika virus (ZIKV) during a visit to Cuba. The infection was confirmed using molecular and serological methods. This report highlights potential drawbacks of using IgG serology for diagnosis of flavivirus infections in endemic regions. [...] Read more.
We report a case of a Singaporean who acquired Zika virus (ZIKV) during a visit to Cuba. The infection was confirmed using molecular and serological methods. This report highlights potential drawbacks of using IgG serology for diagnosis of flavivirus infections in endemic regions. The low viremia detected during the early phase of this case resulted in low mosquito infectivity rates, suggesting the possibility of ZIKV transmission prior to clinical onset. The report also emphasizes the challenges of public health interventions for Zika fever and the importance of sustaining a low vector population to reduce the risk of arbovirus transmission in vulnerable regions. Full article
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17 pages, 2001 KiB  
Article
Identification of Secreted Proteins Involved in Nonspecific dsRNA-Mediated Lutzomyia longipalpis LL5 Cell Antiviral Response
by Andrea Martins-da-Silva, Erich Loza Telleria, Michel Batista, Fabricio Klerynton Marchini, Yara Maria Traub-Csekö and Antonio Jorge Tempone
Viruses 2018, 10(1), 43; https://doi.org/10.3390/v10010043 - 18 Jan 2018
Cited by 11 | Viewed by 5576
Abstract
Hematophagous insects transmit infectious diseases. Sand flies are vectors of leishmaniasis, but can also transmit viruses. We have been studying immune responses of Lutzomyia longipalpis, the main vector of visceral leishmaniasis in the Americas. We identified a non-specific antiviral response in L. [...] Read more.
Hematophagous insects transmit infectious diseases. Sand flies are vectors of leishmaniasis, but can also transmit viruses. We have been studying immune responses of Lutzomyia longipalpis, the main vector of visceral leishmaniasis in the Americas. We identified a non-specific antiviral response in L. longipalpis LL5 embryonic cells when treated with non-specific double-stranded RNAs (dsRNAs). This response is reminiscent of interferon response in mammals. We are investigating putative effectors for this antiviral response. Secreted molecules have been implicated in immune responses, including interferon-related responses. We conducted a mass spectrometry analysis of conditioned medium from LL5 cells 24 and 48 h after dsRNA or mock treatment. We identified 304 proteins. At 24 h, 19 proteins had an abundance equal or greater than 2-fold change, while the levels of 17 proteins were reduced when compared to control cells. At the 48 h time point, these numbers were 33 and 71, respectively. The two most abundant secreted peptides at 24 h in the dsRNA-transfected group were phospholipid scramblase, an interferon-inducible protein that mediates antiviral activity, and forskolin-binding protein (FKBP), a member of the immunophilin family, which mediates the effect of immunosuppressive drugs. The transcription profile of most candidates did not follow the pattern of secreted protein abundance. Full article
(This article belongs to the Special Issue Antiviral Defense in Invertebrates)
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12 pages, 790 KiB  
Article
Vaccinia Virus in Blood Samples of Humans, Domestic and Wild Mammals in Brazil
by Marina G. Peres, Thais S. Bacchiega, Camila M. Appolinário, Acácia F. Vicente, Mateus De Souza Ribeiro Mioni, Bruna L. D. Ribeiro, Clóvis R. S. Fonseca, Vanessa C. Pelícia, Fernando Ferreira, Graziele P. Oliveira, Jonatas S. Abrahão and Jane Megid
Viruses 2018, 10(1), 42; https://doi.org/10.3390/v10010042 - 18 Jan 2018
Cited by 18 | Viewed by 4488
Abstract
Outbreaks of Vaccinia virus (VACV) affecting cattle and humans have been reported in Brazil in the last 15 years, but the origin of outbreaks remains unknown. Although VACV DNA have been already detected in mice (Mus musculus), opossums (Didelphis albiventris [...] Read more.
Outbreaks of Vaccinia virus (VACV) affecting cattle and humans have been reported in Brazil in the last 15 years, but the origin of outbreaks remains unknown. Although VACV DNA have been already detected in mice (Mus musculus), opossums (Didelphis albiventris) and dogs during VACV zoonotic outbreaks, no transmission to cattle or humans from any of these were reported during Brazilian outbreaks. In this work, we assessed the PCR positivity to VACV in blood samples of cows and other domestic mammals, wild rodents and other wild mammals, and humans from areas with or without VACV infection reports. Our results show the detection of VACV DNA in blood samples of cows, horse and opossums, raising important questions about VACV spread. Full article
(This article belongs to the Special Issue Smallpox and Emerging Zoonotic Orthopoxviruses: What Is Coming Next?)
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8 pages, 633 KiB  
Review
Resistance to HIV Integrase Inhibitors: About R263K and E157Q Mutations
by Charlotte Charpentier and Diane Descamps
Viruses 2018, 10(1), 41; https://doi.org/10.3390/v10010041 - 18 Jan 2018
Cited by 30 | Viewed by 6114
Abstract
The use of integrase inhibitors (INI) is increasing in antiretroviral therapies (ART) and INI are not all equal regarding genetic barrier to resistance. The aim of this manuscript was to review main in vivo and in vitro knowledge about two particular integrase resistance-associated [...] Read more.
The use of integrase inhibitors (INI) is increasing in antiretroviral therapies (ART) and INI are not all equal regarding genetic barrier to resistance. The aim of this manuscript was to review main in vivo and in vitro knowledge about two particular integrase resistance-associated mutations: R263K and E157Q. The R263K mutation was the first mutation rarely found selected at time of virological failure in patients failing a first-line dolutegravir-based treatment. Further in vitro studies on R263K mutants showed a moderate increase in phenotypic resistance level and a drastic reduction in viral replicative capacity. No compensatory mutations were evidenced. The E157Q mutation is polymorphic, found between 1.7% and 5.6% of viral sequences issued from ART-naïve patients depending on the viral subtype; as well as acquired resistance emerging at failure of a raltegravir-based regimen in two case reports. We reported data on phenotypic resistance level of E157Q mutants and virological response of patients harboring a E157Q virus initiating an INI-based regimen, showing that dolutegravir might be the most recommended INI in such patients. These findings show that there is still a need for a better understanding of resistance mechanisms to INI and emphasized the importance of genotypic background in viral evolution under drug pressure. Full article
(This article belongs to the Special Issue Homage to Mark Wainberg)
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28 pages, 714 KiB  
Review
CRISPR-Cas Targeting of Host Genes as an Antiviral Strategy
by Shuliang Chen, Xiao Yu and Deyin Guo
Viruses 2018, 10(1), 40; https://doi.org/10.3390/v10010040 - 16 Jan 2018
Cited by 32 | Viewed by 10505
Abstract
Currently, a new gene editing tool—the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) associated (Cas) system—is becoming a promising approach for genetic manipulation at the genomic level. This simple method, originating from the adaptive immune defense system in prokaryotes, has been developed and [...] Read more.
Currently, a new gene editing tool—the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) associated (Cas) system—is becoming a promising approach for genetic manipulation at the genomic level. This simple method, originating from the adaptive immune defense system in prokaryotes, has been developed and applied to antiviral research in humans. Based on the characteristics of virus-host interactions and the basic rules of nucleic acid cleavage or gene activation of the CRISPR-Cas system, it can be used to target both the virus genome and host factors to clear viral reservoirs and prohibit virus infection or replication. Here, we summarize recent progress of the CRISPR-Cas technology in editing host genes as an antiviral strategy. Full article
(This article belongs to the Special Issue Applications of CRISPR Technology in Virology 2018)
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16 pages, 6542 KiB  
Article
Bacteriophage GC1, a Novel Tectivirus Infecting Gluconobacter Cerinus, an Acetic Acid Bacterium Associated with Wine-Making
by Cécile Philippe, Mart Krupovic, Fety Jaomanjaka, Olivier Claisse, Melina Petrel and Claire Le Marrec
Viruses 2018, 10(1), 39; https://doi.org/10.3390/v10010039 - 16 Jan 2018
Cited by 34 | Viewed by 6514
Abstract
The Gluconobacter phage GC1 is a novel member of the Tectiviridae family isolated from a juice sample collected during dry white wine making. The bacteriophage infects Gluconobacter cerinus, an acetic acid bacterium which represents a spoilage microorganism during wine making, mainly because [...] Read more.
The Gluconobacter phage GC1 is a novel member of the Tectiviridae family isolated from a juice sample collected during dry white wine making. The bacteriophage infects Gluconobacter cerinus, an acetic acid bacterium which represents a spoilage microorganism during wine making, mainly because it is able to produce ethyl alcohol and transform it into acetic acid. Transmission electron microscopy revealed tail-less icosahedral particles with a diameter of ~78 nm. The linear double-stranded DNA genome of GC1 (16,523 base pairs) contains terminal inverted repeats and carries 36 open reading frames, only a handful of which could be functionally annotated. These encode for the key proteins involved in DNA replication (protein-primed family B DNA polymerase) as well as in virion structure and assembly (major capsid protein, genome packaging ATPase (adenosine triphosphatase) and several minor capsid proteins). GC1 is the first tectivirus infecting an alphaproteobacterial host and is thus far the only temperate tectivirus of gram-negative bacteria. Based on distinctive sequence and life-style features, we propose that GC1 represents a new genus within the Tectiviridae, which we tentatively named “Gammatectivirus”. Furthermore, GC1 helps to bridge the gap in the sequence space between alphatectiviruses and betatectiviruses. Full article
(This article belongs to the Special Issue Bacteriophage Genomes and Genomics: News from the Wild)
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13 pages, 3927 KiB  
Article
A Built-In CpG Adjuvant in RSV F Protein DNA Vaccine Drives a Th1 Polarized and Enhanced Protective Immune Response
by Yao Ma, Yue-Ying Jiao, Yun-Zhou Yu, Nan Jiang, Ying Hua, Xiu-Juan Zhang, Yuan-Hui Fu, Xiang-Lei Peng, Yan-Peng Zheng, Larry J. Anderson and Jin-Sheng He
Viruses 2018, 10(1), 38; https://doi.org/10.3390/v10010038 - 15 Jan 2018
Cited by 23 | Viewed by 5083
Abstract
Human respiratory syncytial virus (RSV) is the most significant cause of acute lower respiratory infection in children. However, there is no licensed vaccine available. Here, we investigated the effect of five or 20 copies of C-Class of CpG ODN (CpG-C) motif incorporated into [...] Read more.
Human respiratory syncytial virus (RSV) is the most significant cause of acute lower respiratory infection in children. However, there is no licensed vaccine available. Here, we investigated the effect of five or 20 copies of C-Class of CpG ODN (CpG-C) motif incorporated into a plasmid DNA vaccine encoding RSV fusion (F) glycoprotein on the vaccine-induced immune response. The addition of CpG-C motif enhanced serum binding and virus-neutralizing antibody responses in BALB/c mice immunized with the DNA vaccines. Moreover, mice vaccinated with CpG-modified vaccines, especially with the higher 20 copies, resulted in an enhanced shift toward a Th1-biased antibody and T-cell response, a decrease in pulmonary pathology and virus replication, and a decrease in weight loss after RSV challenge. This study suggests that CpG-C motif, cloned into the backbone of DNA vaccine encoding RSV F glycoprotein, functions as a built-in adjuvant capable of improving the efficacy of DNA vaccine against RSV infection. Full article
(This article belongs to the Section Viral Immunology, Vaccines, and Antivirals)
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22 pages, 2184 KiB  
Review
Structural Insights in Multifunctional Papillomavirus Oncoproteins
by Irina Suarez and Gilles Trave
Viruses 2018, 10(1), 37; https://doi.org/10.3390/v10010037 - 15 Jan 2018
Cited by 30 | Viewed by 6698
Abstract
Since their discovery in the mid-eighties, the main papillomavirus oncoproteins E6 and E7 have been recalcitrant to high-resolution structure analysis. However, in the last decade a wealth of three-dimensional information has been gained on both proteins whether free or complexed to host target [...] Read more.
Since their discovery in the mid-eighties, the main papillomavirus oncoproteins E6 and E7 have been recalcitrant to high-resolution structure analysis. However, in the last decade a wealth of three-dimensional information has been gained on both proteins whether free or complexed to host target proteins. Here, we first summarize the diverse activities of these small multifunctional oncoproteins. Next, we review the available structural data and the new insights they provide about the evolution of E6 and E7, their multiple interactions and their functional variability across human papillomavirus (HPV) species. Full article
(This article belongs to the Special Issue Expert Views on HPV Infection)
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21 pages, 1235 KiB  
Review
Interferons: Reprogramming the Metabolic Network against Viral Infection
by Kavita Raniga and Chen Liang
Viruses 2018, 10(1), 36; https://doi.org/10.3390/v10010036 - 13 Jan 2018
Cited by 49 | Viewed by 12083
Abstract
Viruses exploit the host and induce drastic metabolic changes to ensure an optimal environment for replication and the production of viral progenies. In response, the host has developed diverse countermeasures to sense and limit these alterations to combat viral infection. One such host [...] Read more.
Viruses exploit the host and induce drastic metabolic changes to ensure an optimal environment for replication and the production of viral progenies. In response, the host has developed diverse countermeasures to sense and limit these alterations to combat viral infection. One such host mechanism is through interferon signaling. Interferons are cytokines that enhances the transcription of hundreds of interferon-stimulated genes (ISGs) whose products are key players in the innate immune response to viral infection. In addition to their direct targeting of viral components, interferons and ISGs exert profound effects on cellular metabolism. Recent studies have started to illuminate on the specific role of interferon in rewiring cellular metabolism to activate immune cells and limit viral infection. This review reflects on our current understanding of the complex networking that occurs between the virus and host at the interface of cellular metabolism, with a focus on the ISGs in particular, cholesterol-25-hydroxylase (CH25H), spermidine/spermine acetyltransferase 1 (SAT1), indoleamine-2,3-dioxygenase (IDO1) and sterile alpha motif and histidine/aspartic acid domain-containing protein 1 (SAMHD1), which were recently discovered to modulate specific metabolic events and consequently deter viral infection. Full article
(This article belongs to the Special Issue Homage to Mark Wainberg)
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21 pages, 1850 KiB  
Article
Human Cytomegalovirus Nuclear Capsids Associate with the Core Nuclear Egress Complex and the Viral Protein Kinase pUL97
by Jens Milbradt, Eric Sonntag, Sabrina Wagner, Hanife Strojan, Christina Wangen, Tihana Lenac Rovis, Berislav Lisnic, Stipan Jonjic, Heinrich Sticht, William J. Britt, Ursula Schlötzer-Schrehardt and Manfred Marschall
Viruses 2018, 10(1), 35; https://doi.org/10.3390/v10010035 - 13 Jan 2018
Cited by 26 | Viewed by 6716
Abstract
The nuclear phase of herpesvirus replication is regulated through the formation of regulatory multi-component protein complexes. Viral genomic replication is followed by nuclear capsid assembly, DNA encapsidation and nuclear egress. The latter has been studied intensely pointing to the formation of a viral [...] Read more.
The nuclear phase of herpesvirus replication is regulated through the formation of regulatory multi-component protein complexes. Viral genomic replication is followed by nuclear capsid assembly, DNA encapsidation and nuclear egress. The latter has been studied intensely pointing to the formation of a viral core nuclear egress complex (NEC) that recruits a multimeric assembly of viral and cellular factors for the reorganization of the nuclear envelope. To date, the mechanism of the association of human cytomegalovirus (HCMV) capsids with the NEC, which in turn initiates the specific steps of nuclear capsid budding, remains undefined. Here, we provide electron microscopy-based data demonstrating the association of both nuclear capsids and NEC proteins at nuclear lamina budding sites. Specifically, immunogold labelling of the core NEC constituent pUL53 and NEC-associated viral kinase pUL97 suggested an intranuclear NEC-capsid interaction. Staining patterns with phospho-specific lamin A/C antibodies are compatible with earlier postulates of targeted capsid egress at lamina-depleted areas. Important data were provided by co-immunoprecipitation and in vitro kinase analyses using lysates from HCMV-infected cells, nuclear fractions, or infectious virions. Data strongly suggest that nuclear capsids interact with pUL53 and pUL97. Combined, the findings support a refined concept of HCMV nuclear trafficking and NEC-capsid interaction. Full article
(This article belongs to the Section Animal Viruses)
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24 pages, 1689 KiB  
Article
Biomarkers of Progression after HIV Acute/Early Infection: Nothing Compares to CD4+ T-cell Count?
by Gabriela Turk, Yanina Ghiglione, Macarena Hormanstorfer, Natalia Laufer, Romina Coloccini, Jimena Salido, César Trifone, María Julia Ruiz, Juliana Falivene, María Pía Holgado, María Paula Caruso, María Inés Figueroa, Horacio Salomón, Luis D. Giavedoni, María De los Ángeles Pando, María Magdalena Gherardi, Roberto Daniel Rabinovich, Pedro A. Pury and Omar Sued
Viruses 2018, 10(1), 34; https://doi.org/10.3390/v10010034 - 13 Jan 2018
Cited by 11 | Viewed by 5435
Abstract
Progression of HIV infection is variable among individuals, and definition disease progression biomarkers is still needed. Here, we aimed to categorize the predictive potential of several variables using feature selection methods and decision trees. A total of seventy-five treatment-naïve subjects were enrolled during [...] Read more.
Progression of HIV infection is variable among individuals, and definition disease progression biomarkers is still needed. Here, we aimed to categorize the predictive potential of several variables using feature selection methods and decision trees. A total of seventy-five treatment-naïve subjects were enrolled during acute/early HIV infection. CD4+ T-cell counts (CD4TC) and viral load (VL) levels were determined at enrollment and for one year. Immune activation, HIV-specific immune response, Human Leukocyte Antigen (HLA) and C-C chemokine receptor type 5 (CCR5) genotypes, and plasma levels of 39 cytokines were determined. Data were analyzed by machine learning and non-parametric methods. Variable hierarchization was performed by Weka correlation-based feature selection and J48 decision tree. Plasma interleukin (IL)-10, interferon gamma-induced protein (IP)-10, soluble IL-2 receptor alpha (sIL-2Rα) and tumor necrosis factor alpha (TNF-α) levels correlated directly with baseline VL, whereas IL-2, TNF-α, fibroblast growth factor (FGF)-2 and macrophage inflammatory protein (MIP)-1β correlated directly with CD4+ T-cell activation (p < 0.05). However, none of these cytokines had good predictive values to distinguish “progressors” from “non-progressors”. Similarly, immune activation, HIV-specific immune responses and HLA/CCR5 genotypes had low discrimination power. Baseline CD4TC was the most potent discerning variable with a cut-off of 438 cells/μL (accuracy = 0.93, κ-Cohen = 0.85). Limited discerning power of the other factors might be related to frequency, variability and/or sampling time. Future studies based on decision trees to identify biomarkers of post-treatment control are warrantied. Full article
(This article belongs to the Special Issue Homage to Mark Wainberg)
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22 pages, 8514 KiB  
Article
Causation of Acute Flaccid Paralysis by Myelitis and Myositis in Enterovirus-D68 Infected Mice Deficient in Interferon αβ/γ Receptor Deficient Mice
by John D. Morrey, Hong Wang, Brett L. Hurst, Katherine Zukor, Venkatraman Siddharthan, Arnaud J. Van Wettere, Donal G. Sinex and E. Bart Tarbet
Viruses 2018, 10(1), 33; https://doi.org/10.3390/v10010033 - 12 Jan 2018
Cited by 41 | Viewed by 7097
Abstract
Enterovirus D68 (EV-D68) caused a large outbreak in the summer and fall of 2014 in the United States. It causes serious respiratory disease, but causation of associated paralysis is controversial, because the virus is not routinely identified in cerebrospinal fluid. To establish clinical [...] Read more.
Enterovirus D68 (EV-D68) caused a large outbreak in the summer and fall of 2014 in the United States. It causes serious respiratory disease, but causation of associated paralysis is controversial, because the virus is not routinely identified in cerebrospinal fluid. To establish clinical correlates with human disease, we evaluated EV-D68 infection in non-lethal paralysis mouse models. Ten-day-old mice lacking interferon responses were injected intraperitoneally with the virus. Paralysis developed in hindlimbs. After six weeks of paralysis, the motor neurons were depleted due to viral infection. Hindlimb muscles were also infected and degenerating. Even at the earliest stage of paralysis, muscles were still infected and were degenerating, in addition to presence of virus in the spinal cord. To model natural respiratory infection, five-day-old mice were infected intranasally with EV-D68. Two of the four infected mice developed forelimb paralysis. The affected limbs had muscle disease, but no spinal cord infection was detected. The unique contributions of this study are that EV-D68 causes paralysis in mice, and that causation by muscle disease, with or without spinal cord disease, may help to resolve the controversy that the virus can cause paralysis, even if it cannot be identified in cerebrospinal fluid. Full article
(This article belongs to the Section Animal Viruses)
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15 pages, 1564 KiB  
Article
Metagenomic Virome Analysis of Culex Mosquitoes from Kenya and China
by Evans Atoni, Yujuan Wang, Samuel Karungu, Cecilia Waruhiu, Ali Zohaib, Vincent Obanda, Bernard Agwanda, Morris Mutua, Han Xia and Zhiming Yuan
Viruses 2018, 10(1), 30; https://doi.org/10.3390/v10010030 - 12 Jan 2018
Cited by 63 | Viewed by 11907
Abstract
Many blood-feeding arthropods are known vectors of viruses that are a source of unprecedented global health concern. Mosquitoes are an integral part of these arthropod vectors. Advancements in next-generation sequencing and bioinformatics has expanded our knowledge on the richness of viruses harbored by [...] Read more.
Many blood-feeding arthropods are known vectors of viruses that are a source of unprecedented global health concern. Mosquitoes are an integral part of these arthropod vectors. Advancements in next-generation sequencing and bioinformatics has expanded our knowledge on the richness of viruses harbored by arthropods. In the present study, we applied a metagenomic approach to determine the intercontinental virome diversity of Culex quinquefasciatus and Culex tritaeniorhynchus in Kwale, Kenya and provinces of Hubei and Yunnan in China. Our results showed that viromes from the three locations were strikingly diverse and comprised 30 virus families specific to vertebrates, invertebrates, plants, and protozoa as well as unclassified group of viruses. Though sampled at different times, both Kwale and Hubei mosquito viromes were dominated by vertebrate viruses, in contrast to the Yunnan mosquito virome, which was dominated by insect-specific viruses. However, each virome was unique in terms of virus proportions partly influenced by type of ingested meals (blood, nectar, plant sap, environment substrates). The dominant vertebrate virus family in the Kwale virome was Papillomaviridae (57%) while in Hubei it was Herpesviridae (30%) and the Yunnan virome was dominated by an unclassified viruses group (27%). Given that insect-specific viruses occur naturally in their hosts, they should be the basis for defining the viromes. Hence, the dominant insect-specific viruses in Kwale, Hubei, and Yunnan were Baculoviridae, Nimaviridae and Iflaviridae, respectively. Our study is preliminary but contributes to growing and much needed knowledge, as mosquito viromes could be manipulated to prevent and control pathogenic arboviruses. Full article
(This article belongs to the Collection Global Viral Threats)
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11 pages, 441 KiB  
Editorial
Acknowledgement to Reviewers of Viruses in 2017
by Viruses Editorial Office
Viruses 2018, 10(1), 32; https://doi.org/10.3390/v10010032 - 11 Jan 2018
Viewed by 3287
Abstract
Peer review is an essential part in the publication process, ensuring that Viruses maintains high quality standards for its published papers.[...] Full article
14 pages, 3477 KiB  
Article
Phylogenetic Analysis and Characterization of a Sporadic Isolate of Equine Influenza A H3N8 from an Unvaccinated Horse in 2015
by Chithra C. Sreenivasan, Sunayana S. Jandhyala, Sisi Luo, Ben M. Hause, Milton Thomas, David E. B. Knudsen, Pamela Leslie-Steen, Travis Clement, Stephanie E. Reedy, Thomas M. Chambers, Jane Christopher-Hennings, Eric Nelson, Dan Wang, Radhey S. Kaushik and Feng Li
Viruses 2018, 10(1), 31; https://doi.org/10.3390/v10010031 - 11 Jan 2018
Cited by 13 | Viewed by 7521
Abstract
Equine influenza, caused by the H3N8 subtype, is a highly contagious respiratory disease affecting equid populations worldwide and has led to serious epidemics and transboundary pandemics. This study describes the phylogenetic characterization and replication kinetics of recently-isolated H3N8 virus from a nasal swab [...] Read more.
Equine influenza, caused by the H3N8 subtype, is a highly contagious respiratory disease affecting equid populations worldwide and has led to serious epidemics and transboundary pandemics. This study describes the phylogenetic characterization and replication kinetics of recently-isolated H3N8 virus from a nasal swab obtained from a sporadic case of natural infection in an unvaccinated horse from Montana, USA. The nasal swab tested positive for equine influenza by Real-Time Quantitative Reverse Transcription Polymerase Chain Reaction (RT-PCR). Further, the whole genome sequencing of the virus confirmed that it was the H3N8 subtype and was designated as A/equine/Montana/9564-1/2015 (H3N8). A BLASTn search revealed that the polymerase basic protein 1 (PB1), polymerase acidic (PA), hemagglutinin (HA), nucleoprotein (NP), and matrix (M) segments of this H3N8 isolate shared the highest percentage identity to A/equine/Tennessee/29A/2014 (H3N8) and the polymerase basic protein 2 (PB2), neuraminidase (NA), and non-structural protein (NS) segments to A/equine/Malaysia/M201/2015 (H3N8). Phylogenetic characterization of individual gene segments, using currently available H3N8 viral genomes, of both equine and canine origin, further established that A/equine/Montana/9564-1/2015 belonged to the Florida Clade 1 viruses. Interestingly, replication kinetics of this H3N8 virus, using airway derived primary cells from multiple species, such as equine, swine, bovine, and human lung epithelial cells, demonstrated appreciable titers, when compared to Madin–Darby canine kidney epithelial cells. These findings indicate the broad host spectrum of this virus isolate and suggest the potential for cross-species transmissibility. Full article
(This article belongs to the Section Animal Viruses)
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12 pages, 755 KiB  
Review
A Retrospective Examination of Feline Leukemia Subgroup Characterization: Viral Interference Assays to Deep Sequencing
by Elliott S. Chiu, Edward A. Hoover and Sue VandeWoude
Viruses 2018, 10(1), 29; https://doi.org/10.3390/v10010029 - 10 Jan 2018
Cited by 36 | Viewed by 7361
Abstract
Feline leukemia virus (FeLV) was the first feline retrovirus discovered, and is associated with multiple fatal disease syndromes in cats, including lymphoma. The original research conducted on FeLV employed classical virological techniques. As methods have evolved to allow FeLV genetic characterization, investigators have [...] Read more.
Feline leukemia virus (FeLV) was the first feline retrovirus discovered, and is associated with multiple fatal disease syndromes in cats, including lymphoma. The original research conducted on FeLV employed classical virological techniques. As methods have evolved to allow FeLV genetic characterization, investigators have continued to unravel the molecular pathology associated with this fascinating agent. In this review, we discuss how FeLV classification, transmission, and disease-inducing potential have been defined sequentially by viral interference assays, Sanger sequencing, PCR, and next-generation sequencing. In particular, we highlight the influences of endogenous FeLV and host genetics that represent FeLV research opportunities on the near horizon. Full article
(This article belongs to the Section Animal Viruses)
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26 pages, 7322 KiB  
Article
Quantitative Analysis of Hepatitis C NS5A Viral Protein Dynamics on the ER Surface
by Markus M. Knodel, Arne Nägel, Sebastian Reiter, Andreas Vogel, Paul Targett-Adams, John McLauchlan, Eva Herrmann and Gabriel Wittum
Viruses 2018, 10(1), 28; https://doi.org/10.3390/v10010028 - 8 Jan 2018
Cited by 9 | Viewed by 6304
Abstract
Exploring biophysical properties of virus-encoded components and their requirement for virus replication is an exciting new area of interdisciplinary virological research. To date, spatial resolution has only rarely been analyzed in computational/biophysical descriptions of virus replication dynamics. However, it is widely acknowledged that [...] Read more.
Exploring biophysical properties of virus-encoded components and their requirement for virus replication is an exciting new area of interdisciplinary virological research. To date, spatial resolution has only rarely been analyzed in computational/biophysical descriptions of virus replication dynamics. However, it is widely acknowledged that intracellular spatial dependence is a crucial component of virus life cycles. The hepatitis C virus-encoded NS5A protein is an endoplasmatic reticulum (ER)-anchored viral protein and an essential component of the virus replication machinery. Therefore, we simulate NS5A dynamics on realistic reconstructed, curved ER surfaces by means of surface partial differential equations (sPDE) upon unstructured grids. We match the in silico NS5A diffusion constant such that the NS5A sPDE simulation data reproduce experimental NS5A fluorescence recovery after photobleaching (FRAP) time series data. This parameter estimation yields the NS5A diffusion constant. Such parameters are needed for spatial models of HCV dynamics, which we are developing in parallel but remain qualitative at this stage. Thus, our present study likely provides the first quantitative biophysical description of the movement of a viral component. Our spatio-temporal resolved ansatz paves new ways for understanding intricate spatial-defined processes central to specfic aspects of virus life cycles. Full article
(This article belongs to the Special Issue Mathematical Modeling of Viral Infections)
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14 pages, 3010 KiB  
Article
Development of a Surrogate Neutralization Assay for Norovirus Vaccine Evaluation at the Cellular Level
by Xiaoli Wang, Shuxia Wang, Chao Zhang, Yu Zhou, Pei Xiong, Qingwei Liu and Zhong Huang
Viruses 2018, 10(1), 27; https://doi.org/10.3390/v10010027 - 5 Jan 2018
Cited by 9 | Viewed by 5968
Abstract
Noroviruses (NoVs) are the main pathogens responsible for sporadic and epidemic nonbacterial gastroenteritis, causing an estimated 219,000 deaths annually worldwide. There is no commercially available vaccine for NoVs, due partly to the difficulty in establishing NoV cell culture models. The histo-blood group antigen [...] Read more.
Noroviruses (NoVs) are the main pathogens responsible for sporadic and epidemic nonbacterial gastroenteritis, causing an estimated 219,000 deaths annually worldwide. There is no commercially available vaccine for NoVs, due partly to the difficulty in establishing NoV cell culture models. The histo-blood group antigen (HBGA) blocking assay is used extensively to assess the protective potential of candidate vaccine-elicited antibodies, but there is still no widely used cellular evaluation model. In this study, we have established a cell line-based NoV vaccine evaluation model through the construction of human α1,2-fucosyltransferase 2-overexpressing 293T (293T-FUT2) cell lines. The 293T-FUT2 cells stably expressed H type 2 and Lewis y antigens. Virus-like particles (VLPs) of the NoV prototype strain genogroup I.1 (GI.1) and the predominant strains GII.4 and GII.17 could attach to the cell line efficiently in a dose-dependent manner. Importantly, antisera against these NoV VLPs could inhibit the attachment of the VLPs, where the inhibitory effects measured by the attachment inhibition assay correlated significantly with the antibody levels determined by the HBGA blocking assay. Collectively, our attachment inhibition assay could serve as a surrogate neutralization assay for the evaluation of NoV vaccines at the cellular level. Full article
(This article belongs to the Section Viral Immunology, Vaccines, and Antivirals)
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19 pages, 3226 KiB  
Article
High-Mannose But Not Complex-Type Glycosylation of Tetherin Is Required for Restriction of HIV-1 Release
by Abdul A. Waheed, Ariana Gitzen, Maya Swiderski and Eric O. Freed
Viruses 2018, 10(1), 26; https://doi.org/10.3390/v10010026 - 5 Jan 2018
Cited by 12 | Viewed by 4577
Abstract
Tetherin is an interferon-inducible antiviral protein that inhibits the release of a broad spectrum of enveloped viruses by retaining virions at the surface of infected cells. While the role of specific tetherin domains in antiviral activity is clearly established, the role of glycosylation [...] Read more.
Tetherin is an interferon-inducible antiviral protein that inhibits the release of a broad spectrum of enveloped viruses by retaining virions at the surface of infected cells. While the role of specific tetherin domains in antiviral activity is clearly established, the role of glycosylation in tetherin function is not clear. In this study, we carried out a detailed investigation of this question by using tetherin variants in which one or both sites of N-linked glycosylation were mutated (N65A, N92A, and N65,92A), and chemical inhibitors that prevent glycosylation at specific stages of oligosaccharide were added or modified. The single N-linked glycosylation mutants, N65A and N92A, efficiently inhibited the release of Vpu-defective human immunodeficiency virus type 1 (HIV-1). In contrast, the non-glycosylated double mutant, N65,92A, lost its ability to block HIV-1 release. The inability of the N65,92A mutant to inhibit HIV-1 release is associated with a lack of cell-surface expression. A role for glycosylation in cell-surface tetherin expression is supported by tunicamycin treatment, which inhibits the first step of N-linked glycosylation and impairs both cell-surface expression and antiviral activity. Inhibition of complex-type glycosylation with kifunensine, an inhibitor of the oligosaccharide processing enzyme mannosidase 1, had no effect on either the cell-surface expression or antiviral activity of tetherin. These results demonstrate that high-mannose modification of a single asparagine residue is necessary and sufficient, while complex-type glycosylation is dispensable, for cell-surface tetherin expression and antiviral activity. Full article
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9 pages, 1624 KiB  
Review
Geometric Defects and Icosahedral Viruses
by Joseph Che-Yen Wang, Suchetana Mukhopadhyay and Adam Zlotnick
Viruses 2018, 10(1), 25; https://doi.org/10.3390/v10010025 - 4 Jan 2018
Cited by 21 | Viewed by 6976
Abstract
We propose that viruses with geometric defects are not necessarily flawed viruses. A geometric defect may be a reactive site. Defects may facilitate assembly, dissociation, or accessibility of cellular proteins to virion components. In single molecule studies of hepadnavirus assembly, defects and overgrowth [...] Read more.
We propose that viruses with geometric defects are not necessarily flawed viruses. A geometric defect may be a reactive site. Defects may facilitate assembly, dissociation, or accessibility of cellular proteins to virion components. In single molecule studies of hepadnavirus assembly, defects and overgrowth are common features. Icosahedral alphaviruses and flaviviruses, among others, have capsids with geometric defects. Similarly, immature retroviruses, which are non-icosahedral, have numerous “errors”. In many viruses, asymmetric exposure of interior features allows for regulated genome release or supports intracellular trafficking. In these viruses, the defects likely serve a biological function. Commonly used approaches for spherical virus structure determination use symmetry averaging, which obscures defects. We suggest that there are three classes of asymmetry: regular asymmetry as might be found in a tailed phage, irregular asymmetry as found, for example, in defects randomly trapped during assembly, and dynamic asymmetry due to Brownian dynamics of virus capsids. Awareness of their presence and recent advances in electron microscopy will allow unprecedented investigation of capsid irregularities to investigate their biological relevance. Full article
(This article belongs to the Special Issue Advances in Structural Virology via Cryo-EM)
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7 pages, 1090 KiB  
Review
Visualizing the Nucleotide Addition Cycle of Viral RNA-Dependent RNA Polymerase
by Jiqin Wu and Peng Gong
Viruses 2018, 10(1), 24; https://doi.org/10.3390/v10010024 - 4 Jan 2018
Cited by 14 | Viewed by 6160
Abstract
Viral RNA-dependent RNA polymerases (RdRPs) are a class of nucleic acid polymerases bearing unique features from global architecture to catalytic mechanisms. In recent years, numerous viral RdRP crystal structures have improved the understanding of these molecular machines, in particular, for how they carry [...] Read more.
Viral RNA-dependent RNA polymerases (RdRPs) are a class of nucleic acid polymerases bearing unique features from global architecture to catalytic mechanisms. In recent years, numerous viral RdRP crystal structures have improved the understanding of these molecular machines, in particular, for how they carry out each nucleotide addition cycle (NAC) as directed by the RNA template. This review focuses on a visual introduction of viral RdRP NAC mechanisms through a combination of static pictures of structural models, a user-friendly software-based assembly of the structural models, and two videos illustrating key conformational changes in the NAC. Full article
(This article belongs to the Special Issue Structure-Function Relationships in Viral Polymerases)
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6 pages, 1524 KiB  
Letter
Myelin Oligodendrocyte Glycoprotein-Independent Rubella Infection of Keratinocytes and Resistance of First-Trimester Trophoblast Cells to Rubella Virus In Vitro
by Quang Duy Trinh, Ngan Thi Kim Pham, Kazuhide Takada, Shihoko Komine-Aizawa and Satoshi Hayakawa
Viruses 2018, 10(1), 23; https://doi.org/10.3390/v10010023 - 4 Jan 2018
Cited by 11 | Viewed by 6033
Abstract
Rubella virus (RuV), which belongs to the family Togaviridae and genus Rubivirus, causes systemic infection in children and young adults and congenital rubella syndrome in developing fetuses if the infection occurs during pregnancy. The mechanisms of fetal infection by RuV are not [...] Read more.
Rubella virus (RuV), which belongs to the family Togaviridae and genus Rubivirus, causes systemic infection in children and young adults and congenital rubella syndrome in developing fetuses if the infection occurs during pregnancy. The mechanisms of fetal infection by RuV are not completely understood. Myelin oligodendrocyte glycoprotein (MOG) is reported to be a cellular receptor for RuV; however, it is mainly expressed in the central nervous system. Therefore, it is thought that other receptors are also responsible for virus entry into susceptible cells. In this study, we found that first-trimester trophoblast cells were resistant to RuV. In addition, we showed that HaCaT cells (an immortalized keratinocyte cell line) that did not express MOG on their surface were infected with RuV. This finding is one of the first demonstrations of MOG-independent RuV infection of susceptible host cells and suggests that it is important to continue searching for alternative RuV receptors. In addition, this study reports the resistance of first-trimester trophoblast cells to RuV and suggests that utilizing an epithelial–mesenchymal transition approach to study the mechanisms of transplacental vertical RuV infection. Full article
(This article belongs to the Collection Global Viral Threats)
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18 pages, 17196 KiB  
Article
Atomic Resolution Structures of Human Bufaviruses Determined by Cryo-Electron Microscopy
by Maria Ilyas, Mario Mietzsch, Shweta Kailasan, Elina Väisänen, Mengxiao Luo, Paul Chipman, J. Kennon Smith, Justin Kurian, Duncan Sousa, Robert McKenna, Maria Söderlund-Venermo and Mavis Agbandje-McKenna
Viruses 2018, 10(1), 22; https://doi.org/10.3390/v10010022 - 4 Jan 2018
Cited by 18 | Viewed by 10406
Abstract
Bufavirus strain 1 (BuV1), a member of the Protoparvovirus genus of the Parvoviridae, was first isolated from fecal samples of children with acute diarrhea in Burkina Faso. Since this initial discovery, BuVs have been isolated in several countries, including Finland, the Netherlands, [...] Read more.
Bufavirus strain 1 (BuV1), a member of the Protoparvovirus genus of the Parvoviridae, was first isolated from fecal samples of children with acute diarrhea in Burkina Faso. Since this initial discovery, BuVs have been isolated in several countries, including Finland, the Netherlands, and Bhutan, in pediatric patients exhibiting similar symptoms. Towards their characterization, the structures of virus-like particles of BuV1, BuV2, and BuV3, the current known genotypes, have been determined by cryo-electron microscopy and image reconstruction to 2.84, 3.79, and 3.25 Å, respectively. The BuVs, 65–73% identical in amino acid sequence, conserve the major viral protein, VP2, structure and general capsid surface features of parvoviruses. These include a core β-barrel (βB-βI), α-helix A, and large surface loops inserted between these elements in VP2. The capsid contains depressions at the icosahedral 2-fold and around the 5-fold axes, and has three separated protrusions surrounding the 3-fold axes. Structure comparison among the BuVs and to available parvovirus structures revealed capsid surface variations and capsid 3-fold protrusions that depart from the single pinwheel arrangement of the animal protoparvoviruses. These structures provide a platform to begin the molecular characterization of these potentially pathogenic viruses. Full article
(This article belongs to the Special Issue Advances in Structural Virology via Cryo-EM)
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14 pages, 1221 KiB  
Article
E3L and F1L Gene Functions Modulate the Protective Capacity of Modified Vaccinia Virus Ankara Immunization in Murine Model of Human Smallpox
by Asisa Volz, Sylvia Jany, Astrid Freudenstein, Markus Lantermann, Holger Ludwig and Gerd Sutter
Viruses 2018, 10(1), 21; https://doi.org/10.3390/v10010021 - 4 Jan 2018
Cited by 6 | Viewed by 5798
Abstract
The highly attenuated Modified Vaccinia virus Ankara (MVA) lacks most of the known vaccinia virus (VACV) virulence and immune evasion genes. Today MVA can serve as a safety-tested next-generation smallpox vaccine. Yet, we still need to learn about regulatory gene functions preserved in [...] Read more.
The highly attenuated Modified Vaccinia virus Ankara (MVA) lacks most of the known vaccinia virus (VACV) virulence and immune evasion genes. Today MVA can serve as a safety-tested next-generation smallpox vaccine. Yet, we still need to learn about regulatory gene functions preserved in the MVA genome, such as the apoptosis inhibitor genes F1L and E3L. Here, we tested MVA vaccine preparations on the basis of the deletion mutant viruses MVA-ΔF1L and MVA-ΔE3L for efficacy against ectromelia virus (ECTV) challenge infections in mice. In non-permissive human tissue culture the MVA deletion mutant viruses produced reduced levels of the VACV envelope antigen B5. Upon mousepox challenge at three weeks after vaccination, MVA-ΔF1L and MVA-ΔE3L exhibited reduced protective capacity in comparison to wildtype MVA. Surprisingly, however, all vaccines proved equally protective against a lethal ECTV infection at two days after vaccination. Accordingly, the deletion mutant MVA vaccines induced high levels of virus-specific CD8+ T cells previously shown to be essential for rapidly protective MVA vaccination. These results suggest that inactivation of the anti-apoptotic genes F1L or E3L modulates the protective capacity of MVA vaccination most likely through the induction of distinct orthopoxvirus specific immunity in the absence of these viral regulatory proteins. Full article
(This article belongs to the Special Issue Smallpox and Emerging Zoonotic Orthopoxviruses: What Is Coming Next?)
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