Viruses

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Open AccessArticle

IFITM Proteins Inhibit Entry Driven by the MERS-Coronavirus Spike Protein: Evidence for Cholesterol-Independent Mechanisms

by Florian Wrensch, Michael Winkler and Stefan Pöhlmann

Viruses 2014, 6(9), 3683-3698; https://doi.org/10.3390/v6093683 - 26 Sep 2014

Cited by 113 | Viewed by 10205

Abstract

The interferon-inducible transmembrane (IFITM) proteins 1, 2 and 3 inhibit the host cell entry of several enveloped viruses, potentially by promoting the accumulation of cholesterol in endosomal compartments. IFITM3 is essential for control of influenza virus infection in mice and humans. In contrast, [...] Read more.

The interferon-inducible transmembrane (IFITM) proteins 1, 2 and 3 inhibit the host cell entry of several enveloped viruses, potentially by promoting the accumulation of cholesterol in endosomal compartments. IFITM3 is essential for control of influenza virus infection in mice and humans. In contrast, the role of IFITM proteins in coronavirus infection is less well defined. Employing a retroviral vector system for analysis of coronavirus entry, we investigated the susceptibility of human-adapted and emerging coronaviruses to inhibition by IFITM proteins. We found that entry of the recently emerged Middle East respiratory syndrome coronavirus (MERS-CoV) is sensitive to inhibition by IFITM proteins. In 293T cells, IFITM-mediated inhibition of cellular entry of the emerging MERS- and SARS-CoV was less efficient than blockade of entry of the globally circulating human coronaviruses 229E and NL63. Similar differences were not observed in A549 cells, suggesting that cellular context and/or IFITM expression levels can impact inhibition efficiency. The differential IFITM-sensitivity of coronaviruses observed in 293T cells afforded the opportunity to investigate whether efficiency of entry inhibition by IFITMs and endosomal cholesterol accumulation correlate. No such correlation was observed. Furthermore, entry mediated by the influenza virus hemagglutinin was robustly inhibited by IFITM3 but was insensitive to accumulation of endosomal cholesterol, indicating that modulation of cholesterol synthesis/transport did not account for the antiviral activity of IFITM3. Collectively, these results show that the emerging MERS-CoV is a target of the antiviral activity of IFITM proteins and demonstrate that mechanisms other than accumulation of endosomal cholesterol can contribute to viral entry inhibition by IFITMs. Full article

(This article belongs to the Section Animal Viruses)

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Open AccessLetter

Filovirus RefSeq Entries: Evaluation and Selection of Filovirus Type Variants, Type Sequences, and Names

by Jens H. Kuhn, Kristian G. Andersen, Yīmíng Bào, Sina Bavari, Stephan Becker, Richard S. Bennett, Nicholas H. Bergman, Olga Blinkova, Steven Bradfute, J. Rodney Brister, Alexander Bukreyev, Kartik Chandran, Alexander A. Chepurnov, Robert A. Davey, Ralf G. Dietzgen, Norman A. Doggett, Olga Dolnik, John M. Dye, Sven Enterlein, Paul W. Fenimore, Pierre Formenty, Alexander N. Freiberg, Robert F. Garry, Nicole L. Garza, Stephen K. Gire, Jean-Paul Gonzalez, Anthony Griffiths, Christian T. Happi, Lisa E. Hensley, Andrew S. Herbert, Michael C. Hevey, Thomas Hoenen, Anna N. Honko, Georgy M. Ignatyev, Peter B. Jahrling, Joshua C. Johnson, Karl M. Johnson, Jason Kindrachuk, Hans-Dieter Klenk, Gary Kobinger, Tadeusz J. Kochel, Matthew G. Lackemeyer, Daniel F. Lackner, Eric M. Leroy, Mark S. Lever, Elke Mühlberger, Sergey V. Netesov, Gene G. Olinger, Sunday A. Omilabu, Gustavo Palacios, Rekha G. Panchal, Daniel J. Park, Jean L. Patterson, Janusz T. Paweska, Clarence J. Peters, James Pettitt, Louise Pitt, Sheli R. Radoshitzky, Elena I. Ryabchikova, Erica Ollmann Saphire, Pardis C. Sabeti, Rachel Sealfon, Aleksandr M. Shestopalov, Sophie J. Smither, Nancy J. Sullivan, Robert Swanepoel, Ayato Takada, Jonathan S. Towner, Guido Van der Groen, Viktor E. Volchkov, Valentina A. Volchkova, Victoria Wahl-Jensen, Travis K. Warren, Kelly L. Warfield, Manfred Weidmann and Stuart T. Nichol Show full author list Hide full author list

Viruses 2014, 6(9), 3663-3682; https://doi.org/10.3390/v6093663 - 26 Sep 2014

Cited by 48 | Viewed by 15717

Abstract

Sequence determination of complete or coding-complete genomes of viruses is becoming common practice for supporting the work of epidemiologists, ecologists, virologists, and taxonomists. Sequencing duration and costs are rapidly decreasing, sequencing hardware is under modification for use by non-experts, and software is constantly [...] Read more.

Sequence determination of complete or coding-complete genomes of viruses is becoming common practice for supporting the work of epidemiologists, ecologists, virologists, and taxonomists. Sequencing duration and costs are rapidly decreasing, sequencing hardware is under modification for use by non-experts, and software is constantly being improved to simplify sequence data management and analysis. Thus, analysis of virus disease outbreaks on the molecular level is now feasible, including characterization of the evolution of individual virus populations in single patients over time. The increasing accumulation of sequencing data creates a management problem for the curators of commonly used sequence databases and an entry retrieval problem for end users. Therefore, utilizing the data to their fullest potential will require setting nomenclature and annotation standards for virus isolates and associated genomic sequences. The National Center for Biotechnology Information’s (NCBI’s) RefSeq is a non-redundant, curated database for reference (or type) nucleotide sequence records that supplies source data to numerous other databases. Building on recently proposed templates for filovirus variant naming [<virus name> (<strain>)/<isolation host-suffix>/<country of sampling>/<year of sampling>/<genetic variant designation>-<isolate designation>], we report consensus decisions from a majority of past and currently active filovirus experts on the eight filovirus type variants and isolates to be represented in RefSeq, their final designations, and their associated sequences. Full article

(This article belongs to the Collection Advances in Ebolavirus, Marburgvirus, and Cuevavirus Research)

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Graphical abstract

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Open AccessMeeting Report

The Ins and Outs of Viral Infection: Keystone Meeting Review

by Sara W. Bird, Karla Kirkegaard, Mavis Agbandje-McKenna and Eric O. Freed

Viruses 2014, 6(9), 3652-3662; https://doi.org/10.3390/v6093652 - 25 Sep 2014

Cited by 3 | Viewed by 6584

Abstract

Newly observed mechanisms for viral entry, assembly, and exit are challenging our current understanding of the replication cycle of different viruses. To address and better understand these mechanisms, a Keystone Symposium was organized in the snowy mountains of Colorado (“The Ins and Outs [...] Read more.

Newly observed mechanisms for viral entry, assembly, and exit are challenging our current understanding of the replication cycle of different viruses. To address and better understand these mechanisms, a Keystone Symposium was organized in the snowy mountains of Colorado (“The Ins and Outs of Viral Infection: Entry, Assembly, Exit, and Spread”; 30 March–4 April 2014, Beaver Run Resort, Breckenridge, Colorado, organized by Karla Kirkegaard, Mavis Agbandje-McKenna, and Eric O. Freed). The meeting served to bring together cell biologists, structural biologists, geneticists, and scientists expert in viral pathogenesis to discuss emerging mechanisms of viral ins and outs. The conference was organized around different phases of the viral replication cycle, including cell entry, viral assembly and post-assembly maturation, virus structure, cell exit, and virus spread. This review aims to highlight important topics and themes that emerged during the conference. Full article

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Open AccessCommentary

Stepping toward a Macaque Model of HIV-1 Induced AIDS

by Jason T. Kimata

Viruses 2014, 6(9), 3643-3651; https://doi.org/10.3390/v6093643 - 25 Sep 2014

Cited by 5 | Viewed by 5627

Abstract

HIV-1 exhibits a narrow host range, hindering the development of a robust animal model of pathogenesis. Past studies have demonstrated that the restricted host range of HIV-1 may be largely due to the inability of the virus to antagonize and evade effector molecules [...] Read more.

HIV-1 exhibits a narrow host range, hindering the development of a robust animal model of pathogenesis. Past studies have demonstrated that the restricted host range of HIV-1 may be largely due to the inability of the virus to antagonize and evade effector molecules of the interferon response in other species. They have also guided the engineering of HIV-1 clones that can replicate in CD4 T-cells of Asian macaque species. However, while replication of these viruses in macaque hosts is persistent, it has been limited and without progression to AIDS. In a new study, Hatziioannou et al., demonstrate for the first time that adapted macaque-tropic HIV-1 can persistently replicate at high levels in pigtailed macaques (Macaca nemestrina), but only if CD8 T-cells are depleted at the time of inoculation. The infection causes rapid disease and recapitulates several aspects of AIDS in humans. Additionally, the virus undergoes genetic changes to further escape innate immunity in association with disease progression. Here, the importance of these findings is discussed, as they relate to pathogenesis and model development. Full article

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Open AccessReview

Retroviral Vectors for Analysis of Viral Mutagenesis and Recombination

by Jonathan M.O. Rawson and Louis M. Mansky

Viruses 2014, 6(9), 3612-3642; https://doi.org/10.3390/v6093612 - 24 Sep 2014

Cited by 6 | Viewed by 7638

Abstract

Retrovirus population diversity within infected hosts is commonly high due in part to elevated rates of replication, mutation, and recombination. This high genetic diversity often complicates the development of effective diagnostics, vaccines, and antiviral drugs. This review highlights the diverse vectors and approaches [...] Read more.

Retrovirus population diversity within infected hosts is commonly high due in part to elevated rates of replication, mutation, and recombination. This high genetic diversity often complicates the development of effective diagnostics, vaccines, and antiviral drugs. This review highlights the diverse vectors and approaches that have been used to examine mutation and recombination in retroviruses. Retroviral vectors for these purposes can broadly be divided into two categories: those that utilize reporter genes as mutation or recombination targets and those that utilize viral genes as targets of mutation or recombination. Reporter gene vectors greatly facilitate the detection, quantification, and characterization of mutants and/or recombinants, but may not fully recapitulate the patterns of mutagenesis or recombination observed in native viral gene sequences. In contrast, the detection of mutations or recombination events directly in viral genes is more biologically relevant but also typically more challenging and inefficient. We will highlight the advantages and disadvantages of the various vectors and approaches used as well as propose ways in which they could be improved. Full article

(This article belongs to the Special Issue Retroviral Vectors)

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Open AccessReview

The Role of Ubiquitin and Ubiquitin-Like Modification Systems in Papillomavirus Biology

by Van G. Wilson

Viruses 2014, 6(9), 3584-3611; https://doi.org/10.3390/v6093584 - 24 Sep 2014

Cited by 8 | Viewed by 6733

Abstract

Human papillomaviruses (HPVs) are small DNA viruses that are important etiological agents of a spectrum of human skin lesions from benign to malignant. Because of their limited genome coding capacity they express only a small number of proteins, only one of which has [...] Read more.

Human papillomaviruses (HPVs) are small DNA viruses that are important etiological agents of a spectrum of human skin lesions from benign to malignant. Because of their limited genome coding capacity they express only a small number of proteins, only one of which has enzymatic activity. Additionally, the HPV productive life cycle is intimately tied to the epithelial differentiation program and they must replicate in what are normally non-replicative cells, thus, these viruses must reprogram the cellular environment to achieve viral reproduction. Because of these limitations and needs, the viral proteins have evolved to co-opt cellular processes primarily through protein-protein interactions with critical host proteins. The ubiquitin post-translational modification system and the related ubiquitin-like modifiers constitute a widespread cellular regulatory network that controls the levels and functions of thousands of proteins, making these systems an attractive target for viral manipulation. This review describes the interactions between HPVs and the ubiquitin family of modifiers, both to regulate the viral proteins themselves and to remodel the host cell to facilitate viral survival and reproduction. Full article

(This article belongs to the Special Issue Viruses and the Ubiquitin/Proteasome System)

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Open AccessReview

The Adenovirus Genome Contributes to the Structural Stability of the Virion

by Bratati Saha, Carmen M. Wong and Robin J. Parks

Viruses 2014, 6(9), 3563-3583; https://doi.org/10.3390/v6093563 - 24 Sep 2014

Cited by 47 | Viewed by 17139

Abstract

Adenovirus (Ad) vectors are currently the most commonly used platform for therapeutic gene delivery in human gene therapy clinical trials. Although these vectors are effective, many researchers seek to further improve the safety and efficacy of Ad-based vectors through detailed characterization of basic [...] Read more.

Adenovirus (Ad) vectors are currently the most commonly used platform for therapeutic gene delivery in human gene therapy clinical trials. Although these vectors are effective, many researchers seek to further improve the safety and efficacy of Ad-based vectors through detailed characterization of basic Ad biology relevant to its function as a vector system. Most Ad vectors are deleted of key, or all, viral protein coding sequences, which functions to not only prevent virus replication but also increase the cloning capacity of the vector for foreign DNA. However, radical modifications to the genome size significantly decreases virion stability, suggesting that the virus genome plays a role in maintaining the physical stability of the Ad virion. Indeed, a similar relationship between genome size and virion stability has been noted for many viruses. This review discusses the impact of the genome size on Ad virion stability and emphasizes the need to consider this aspect of virus biology in Ad-based vector design. Full article

(This article belongs to the Special Issue Adenoviral Vectors)

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Open AccessReview

Drug Resistance in Non-B Subtype HIV-1: Impact of HIV-1 Reverse Transcriptase Inhibitors

by Kamalendra Singh, Jacqueline A. Flores, Karen A. Kirby, Ujjwal Neogi, Anders Sonnerborg, Atsuko Hachiya, Kalyan Das, Eddy Arnold, Carole McArthur, Michael Parniak and Stefan G. Sarafianos

Viruses 2014, 6(9), 3535-3562; https://doi.org/10.3390/v6093535 - 24 Sep 2014

Cited by 28 | Viewed by 15960

Abstract

Human immunodeficiency virus (HIV) causes approximately 2.5 million new infections every year, and nearly 1.6 million patients succumb to HIV each year. Several factors, including cross-species transmission and error-prone replication have resulted in extraordinary genetic diversity of HIV groups. One of these groups, [...] Read more.

Human immunodeficiency virus (HIV) causes approximately 2.5 million new infections every year, and nearly 1.6 million patients succumb to HIV each year. Several factors, including cross-species transmission and error-prone replication have resulted in extraordinary genetic diversity of HIV groups. One of these groups, known as group M (main) contains nine subtypes (A-D, F-H and J-K) and causes ~95% of all HIV infections. Most reported data on susceptibility and resistance to anti-HIV therapies are from subtype B HIV infections, which are prevalent in developed countries but account for only ~12% of all global HIV infections, whereas non-B subtype HIV infections that account for ~88% of all HIV infections are prevalent primarily in low and middle-income countries. Although the treatments for subtype B infections are generally effective against non-B subtype infections, there are differences in response to therapies. Here, we review how polymorphisms, transmission efficiency of drug-resistant strains, and differences in genetic barrier for drug resistance can differentially alter the response to reverse transcriptase-targeting therapies in various subtypes. Full article

(This article belongs to the Special Issue HIV Drug Resistance)

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Open AccessReview

Role of microRNAs in Arbovirus/Vector Interactions

by Sassan Asgari

Viruses 2014, 6(9), 3514-3534; https://doi.org/10.3390/v6093514 - 23 Sep 2014

Cited by 48 | Viewed by 9770

Abstract

The role of microRNAs (miRNAs) as small non-coding RNAs in regulation of gene expression has been recognized. They appear to be involved in regulation of a wide range of cellular pathways that affect several biological processes such as development, the immune system, survival, [...] Read more.

The role of microRNAs (miRNAs) as small non-coding RNAs in regulation of gene expression has been recognized. They appear to be involved in regulation of a wide range of cellular pathways that affect several biological processes such as development, the immune system, survival, metabolism and host-pathogen interactions. Arthropod-borne viruses impose great economic and health risks around the world. Recent advances in miRNA biology have shed some light on the role of these small RNAs in vector-virus interactions. In this review, I will reflect on our current knowledge on the role of miRNAs in arbovirus-vector interactions and the potential avenues for their utilization in limiting virus replication and/or transmission. Full article

(This article belongs to the Special Issue Interactions between Arboviruses and Arthropod Vectors)

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Open AccessMeeting Report

1^st International Symposium on Stress-Associated RNA Granules in Human Disease and Viral Infection

by Bruce W. Banfield, Andrew J. Mouland and Craig McCormick

Viruses 2014, 6(9), 3500-3513; https://doi.org/10.3390/v6093500 - 23 Sep 2014

Cited by 8 | Viewed by 7471

Abstract

In recent years, important linkages have been made between RNA granules and human disease processes. On June 8-10 of this year, we hosted a new symposium, dubbed the 1^st International Symposium on Stress-Associated RNA Granules in Human Disease and Viral Infection. This [...] Read more.

In recent years, important linkages have been made between RNA granules and human disease processes. On June 8-10 of this year, we hosted a new symposium, dubbed the 1^st International Symposium on Stress-Associated RNA Granules in Human Disease and Viral Infection. This symposium brought together experts from diverse research disciplines ranging from cancer and neuroscience to infectious disease. This report summarizes speaker presentations and highlights current challenges in the field. Full article

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Open AccessArticle

Fitness Impaired Drug Resistant HIV-1 Is Not Compromised in Cell-to-Cell Transmission or Establishment of and Reactivation from Latency

by Sophie M. Bastarache, Thibault Mesplède, Daniel A. Donahue, Richard D. Sloan and Mark A. Wainberg

Viruses 2014, 6(9), 3487-3499; https://doi.org/10.3390/v6093487 - 19 Sep 2014

Cited by 12 | Viewed by 6191

Abstract

Both the presence of latently infected cells and cell-to-cell viral transmission are means whereby HIV can partially evade the inhibitory activities of antiretroviral drugs. The clinical use of a novel integrase inhibitor, dolutegravir (DTG), has established hope that this compound may limit HIV [...] Read more.

Both the presence of latently infected cells and cell-to-cell viral transmission are means whereby HIV can partially evade the inhibitory activities of antiretroviral drugs. The clinical use of a novel integrase inhibitor, dolutegravir (DTG), has established hope that this compound may limit HIV persistence, since no treatment-naïve patient treated with DTG has yet developed resistance against this drug, even though a R263K substitution in integrase confers low-level resistance to this drug in tissue culture. Here, we have studied the impact of R263K on HIV replication capacity and the ability of HIV to establish or be reactivated from latency and/or spread through cell-to-cell transmission. We affirm that DTG-resistant viruses have diminished capacity to replicate and establish infection. However, DTG-resistant viruses were efficiently transmitted via cell-to-cell contacts, and were as likely to establish and be reactivated from latent infection as wildtype viruses. Both cell-to-cell transmission of HIV and the establishment of and reemergence from latency are important for the establishment and maintenance of viral reservoirs. Since the DTG and other drug-resistant viruses studied here do not seem to have been impaired in regard to these activities, studies should be undertaken to characterize HIV reservoirs in patients who have been treated with DTG. Full article

(This article belongs to the Special Issue HIV Latency)

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Open AccessReview

Contribution of Viral Mimics of Cellular Genes to KSHV Infection and Disease

by Shuhei Sakakibara and Giovanna Tosato

Viruses 2014, 6(9), 3472-3486; https://doi.org/10.3390/v6093472 - 19 Sep 2014

Cited by 6 | Viewed by 7036

Abstract

Kaposi’s sarcoma-associated herpesvirus (KSHV, also named Human herpesvirus 8 HHV-8) is the cause of Kaposi sarcoma (KS), the most common malignancy in HIV-infected individuals worldwide, primary effusion lymphoma (PEL) and multicentric Castleman disease (MCD). KSHV is a double-stranded DNA virus that encodes several [...] Read more.

Kaposi’s sarcoma-associated herpesvirus (KSHV, also named Human herpesvirus 8 HHV-8) is the cause of Kaposi sarcoma (KS), the most common malignancy in HIV-infected individuals worldwide, primary effusion lymphoma (PEL) and multicentric Castleman disease (MCD). KSHV is a double-stranded DNA virus that encodes several homologues of cellular proteins. The structural similarity between viral and host proteins explains why some viral homologues function as their host counterparts, but sometimes at unusual anatomical sites and inappropriate times. In other cases, structural modification in the viral proteins can suppress or override the function of the host homologue, contributing to KSHV-related diseases. For example, viral IL-6 (vIL-6) is sufficiently different from human IL-6 to activate gp130 signaling independent of the α subunit. As a consequence, vIL-6 can activate many cell types that are unresponsive to cellular IL-6, contributing to MCD disease manifestations. Here, we discuss the molecular biology of KSHV homologues of cellular products as conduits of virus/host interaction with a focus on identifying new strategies for therapy of KS and other KSHV-related diseases. Full article

(This article belongs to the Special Issue Kaposi's Sarcoma-Associated Herpesvirus)

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Open AccessReview

A Filtration Based Technique for Simultaneous SEM and TEM Sample Preparation for the Rapid Detection of Pathogens

by Daniel R. Beniac, Christine G. Siemens, Christine J. Wright and Tim F. Booth

Viruses 2014, 6(9), 3458-3471; https://doi.org/10.3390/v6093458 - 19 Sep 2014

Cited by 25 | Viewed by 31350

Abstract

Diagnostic electron microscopy for infectious diseases has the advantage that “everything” in the specimen can be observed, without a priori knowledge of the likely identity of the microorganisms present in the sample. The classical specimen preparation method used employs a droplet of sample, [...] Read more.

Diagnostic electron microscopy for infectious diseases has the advantage that “everything” in the specimen can be observed, without a priori knowledge of the likely identity of the microorganisms present in the sample. The classical specimen preparation method used employs a droplet of sample, which allows particles to adsorb to a support film, and is subsequently negative stained. This “grid on drop” procedure has a sensitivity range of approximately 10⁶ viruses per mL if no enrichment procedures are used. In the current investigation we present a novel use of filtration that allows us to detect viruses at concentrations as low as 10² viruses per mL. We present here methods based on filtration, in which total virus, and not virus concentration, is the limiting factor for detection. We show that filtration is more sensitive than conventional negative staining and can detect as few as 5 × 10³ particles per sample. Full article

(This article belongs to the Special Issue Electron Microscopy in Virus Diagnostics and Research)

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Open AccessArticle

Detection and Identification of the First Viruses in Chia (Salvia hispanica)

by Marcos G. Celli, Maria C. Perotto, Julia A. Martino, Ceferino R. Flores, Vilma C. Conci and Patricia Rodriguez Pardina

Viruses 2014, 6(9), 3450-3457; https://doi.org/10.3390/v6093450 - 19 Sep 2014

Cited by 14 | Viewed by 9649

Abstract

Chia (Salvia hispanica), an herbaceous plant native to Latin America, has become important in the last 20 years due to its beneficial effects on health. Here, we present the first record and identification of two viruses in chia plants. The comparison [...] Read more.

Chia (Salvia hispanica), an herbaceous plant native to Latin America, has become important in the last 20 years due to its beneficial effects on health. Here, we present the first record and identification of two viruses in chia plants. The comparison of the complete nucleotide sequences showed the presence of two viral species with the typical genome organization of bipartite New World begomovirus, identified as Sida mosaic Bolivia virus 2 and Tomato yellow spot virus, according to the ICTV taxonomic criteria for begomovirus classification. DNA-A from Sida mosaic Bolivia virus 2 exhibited 96.1% nucleotide identity with a Bolivian isolate of Sida micrantha, and Tomato yellow spot virus showed 95.3% nucleotide identity with an Argentine bean isolate. This is the first report of begomoviruses infecting chia as well as of the occurrence of Sida mosaic Bolivia virus 2 in Argentina. Full article

(This article belongs to the Section Viruses of Plants, Fungi and Protozoa)

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Open AccessCommentary

Unusual Influenza A Viruses in Bats

by Andrew Mehle

Viruses 2014, 6(9), 3438-3449; https://doi.org/10.3390/v6093438 - 17 Sep 2014

Cited by 28 | Viewed by 7395

Abstract

Influenza A viruses infect a remarkably diverse number of hosts. Two completely new influenza A virus subtypes were recently discovered in bats, dramatically expanding the host range of the virus. These bat viruses are extremely divergent from all other known strains and likely [...] Read more.

Influenza A viruses infect a remarkably diverse number of hosts. Two completely new influenza A virus subtypes were recently discovered in bats, dramatically expanding the host range of the virus. These bat viruses are extremely divergent from all other known strains and likely have unique replication cycles. Phylogenetic analysis indicates long-term, isolated evolution in bats. This is supported by a high seroprevalence in sampled bat populations. As bats represent ~20% of all classified mammals, these findings suggests the presence of a massive cryptic reservoir of poorly characterized influenza A viruses. Here, we review the exciting progress made on understanding these newly discovered viruses, and discuss their zoonotic potential. Full article

(This article belongs to the Special Issue Viruses and Bats)

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Open AccessArticle

Low-Frequency NNRTI-Resistant HIV-1 Variants and Relationship to Mutational Load in Antiretroviral-Naïve Subjects

by Shaili Gupta, Max Lataillade, Tassos C. Kyriakides, Jennifer Chiarella, Elizabeth P. St. John, Suzin Webb, Elizabeth A. Moreno, Birgitte B. Simen and Michael J. Kozal

Viruses 2014, 6(9), 3428-3437; https://doi.org/10.3390/v6093428 - 16 Sep 2014

Cited by 15 | Viewed by 6080

Abstract

Low-frequency HIV variants possessing resistance mutations against non‑nucleoside reverse transcriptase inhibitors (NNRTI), especially at HIV reverse transcriptase (RT) amino acid (aa) positions K103 and Y181, have been shown to adversely affect treatment response. Therapeutic failure correlates with both the mutant viral variant frequency [...] Read more.

Low-frequency HIV variants possessing resistance mutations against non‑nucleoside reverse transcriptase inhibitors (NNRTI), especially at HIV reverse transcriptase (RT) amino acid (aa) positions K103 and Y181, have been shown to adversely affect treatment response. Therapeutic failure correlates with both the mutant viral variant frequency and the mutational load. We determined the prevalence of NNRTI resistance mutations at several RT aa positions in viruses from 204 antiretroviral (ARV)-naïve HIV-infected individuals using deep sequencing, and examined the relationship between mutant variant frequency and mutational load for those variants. Deep sequencing to ≥0.4% levels found variants with major NNRTI-resistance mutations having a Stanford-HIVdb algorithm value ≥30 for efavirenz and/or nevirapine in 52/204 (25.5%) ARV-naïve HIV-infected persons. Eighteen different major NNRTI mutations were identified at 11 different positions, with the majority of variants being at frequency >1%. The frequency of these variants correlated strongly with the mutational load, but this correlation weakened at low frequencies. Deep sequencing detected additional major NNRTI-resistant viral variants in treatment-naïve HIV-infected individuals. Our study suggests the significance of screening for mutations at all RT aa positions (in addition to K103 and Y181) to estimate the true burden of pre-treatment NNRTI-resistance. An important finding was that variants at low frequency had a wide range of mutational loads (>100-fold) suggesting that frequency alone may underestimate the impact of specific NNRTI-resistant variants. We recommend further evaluation of all low-frequency NNRTI-drug resistant variants with special attention given to the impact of mutational loads of these variants on treatment outcomes. Full article

(This article belongs to the Special Issue HIV Drug Resistance)

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Open AccessReply

Reply to Comment Clement et al.: (Prevalence of Antibodies against Hantaviruses in Serum and Saliva of Adults Living or Working on Farms in Yorkshire, United Kingdom)

by Lisa J. Jameson, Autilia Newton, Louise Coole, Edmund N. C. Newman, Miles W. Carroll, Nick J. Beeching, Roger Hewson and Robert M. Christley

Viruses 2014, 6(9), 3425-3427; https://doi.org/10.3390/v6093425 - 12 Sep 2014

Cited by 1 | Viewed by 4898

Abstract

We acknowledge Clement and colleagues for their comments [1] on our paper [2]. We agree that many controversies are being discussed by the hantavirus community, particularly surrounding the interpretation of serological results and the designation of new species and strains. Within this setting, [...] Read more.

We acknowledge Clement and colleagues for their comments [1] on our paper [2]. We agree that many controversies are being discussed by the hantavirus community, particularly surrounding the interpretation of serological results and the designation of new species and strains. Within this setting, we are grateful for the opportunity to respond to the key factual and methodological points raised by Clements et al. [...] Full article

(This article belongs to the Section Animal Viruses)

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Open AccessComment

Comment on Jameson et al.: Prevalence of Antibodies against Hantaviruses in Serum and Saliva of Adults Living or Working on Farms in Yorkshire, United Kingdom

by Jan Clement, Paula McKenna, Valentijn Vergote and Marc Van Ranst

Viruses 2014, 6(9), 3415-3424; https://doi.org/10.3390/v6093415 - 12 Sep 2014

Cited by 3 | Viewed by 4923

Abstract

This British hantavirus IgG prevalence study, aimed at 119 asymptomatic farmers in England, and using indirect immunofluorescence assay (IFA) as screening technique, concluded that rat-transmitted Seoul virus (SEOV) might be the main suspect as hantaviral pathogen in the UK. Exactly the same conclusion, [...] Read more.

This British hantavirus IgG prevalence study, aimed at 119 asymptomatic farmers in England, and using indirect immunofluorescence assay (IFA) as screening technique, concluded that rat-transmitted Seoul virus (SEOV) might be the main suspect as hantaviral pathogen in the UK. Exactly the same conclusion, using the same IFA screening technique, resulted from a 1994 serosurvey in the same country, and in 627 clinical cases plus 100 healthy controls. SEOV-positive study subjects were also mainly farmers with heavy rat-exposure, but residing in Northern-Ireland, a region where all other known rodent reservoirs for pathogenic hantaviruses are known to be absent, except the wild rat. A rodent capture action in and around the farms of eight seropositives confirmed SEOV seropositivity in 21.6% of 51 rats. All SEOV seropositives were patients, hospitalized with an acute feverish condition, a majority of which having the clinical picture of hantavirus-induced nephropathy, known as hemorrhagic fever with renal syndrome (HFRS). Leptospirosis, often mimicking perfectly HFRS, was serologically excluded. Thus, SEOV was established as a human hantaviral pathogen in the UK and in Europe 20 years ago. Full article

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Open AccessArticle

HIV-1 Env-Specific Memory and Germinal Center B Cells in C57BL/6 Mice

by Martina Soldemo, Gabriel K. Pedersen and Gunilla B. Karlsson Hedestam

Viruses 2014, 6(9), 3400-3414; https://doi.org/10.3390/v6093400 - 5 Sep 2014

Cited by 6 | Viewed by 8638

Abstract

Continued efforts to define the immunogenic properties of the HIV-1 envelope glycoproteins (Env) are needed to elicit effective antibody (Ab) responses by vaccination. HIV-1 is a highly neutralization-resistant virus due to conformational and glycan shielding of conserved Ab determinants on the virus spike. [...] Read more.

Continued efforts to define the immunogenic properties of the HIV-1 envelope glycoproteins (Env) are needed to elicit effective antibody (Ab) responses by vaccination. HIV-1 is a highly neutralization-resistant virus due to conformational and glycan shielding of conserved Ab determinants on the virus spike. Elicitation of broadly neutralizing Abs that bind poorly accessible epitope regions on Env is therefore extremely challenging and will likely require selective targeting of specific sub-determinants. To evaluate such approaches there is a pressing need for in vivo studies in both large and small animals, including mice. Currently, most mouse immunization studies are performed in the BALB/c strain; however, the C57BL/6 strain offers improved possibilities for mechanistic studies due to the availability of numerous knock-out strains on this genetic background. Here, we compared Env immunogenicity in BALB/c and C57BL/6 mice and found that the magnitude of the antigen-specific response was somewhat lower in C57BL/6 than in BALB/c mice by ELISA but not significantly different by B cell ELISpot measurements. We then established protocols for the isolation of single Env-specific memory B cells and germinal center (GC) B cells from immunized C57BL/6 mice to facilitate future studies of the elicited response at the monoclonal Ab level. We propose that these protocols can be used to gain an improved understanding of the early recruitment of Env-specific B cells to the GC as well as the archiving of such responses in the memory B cell pool following immunization. Full article

(This article belongs to the Special Issue AIDS Vaccine 2014)

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Open AccessArticle

Seroprevalence Dynamics of European Bat Lyssavirus Type 1 in a Multispecies Bat Colony

by Marc López-Roig, Hervé Bourhy, Rachel Lavenir and Jordi Serra-Cobo

Viruses 2014, 6(9), 3386-3399; https://doi.org/10.3390/v6093386 - 4 Sep 2014

Cited by 16 | Viewed by 6300

Abstract

We report an active surveillance study of the occurrence of specific antibodies to European Bat Lyssavirus Type 1 (EBLV-1) in bat species, scarcely studied hitherto, that share the same refuge. From 2004 to 2012, 406 sera were obtained from nine bat species. Blood [...] Read more.

We report an active surveillance study of the occurrence of specific antibodies to European Bat Lyssavirus Type 1 (EBLV-1) in bat species, scarcely studied hitherto, that share the same refuge. From 2004 to 2012, 406 sera were obtained from nine bat species. Blood samples were subjected to a modified fluorescent antibody virus neutralization test to determine the antibody titer. EBLV-1-neutralizing antibodies were detected in six of the nine species analyzed (Pipistrellus pipistrellus, P. kuhlii, Hypsugo savii, Plecotus austriacus, Eptesicus serotinus and Tadarida teniotis). Among all bats sampled, female seroprevalence (20.21%, 95% CI: 14.78%–26.57%) was not significantly higher than the seroprevalence in males (15.02%, 95% CI: 10.51%–20.54%). The results showed that the inter-annual variation in the number of seropositive bats in T. teniotis and P. austriacus showed a peak in 2007 (>70% of EBLV-1 prevalence). However, significant differences were observed in the temporal patterns of the seroprevalence modeling of T. teniotis and P. austriacus. The behavioral ecology of these species involved could explain the different annual fluctuations in EBLV-1 seroprevalence. Full article

(This article belongs to the Special Issue Viruses and Bats)

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Open AccessReview

Is Resistance to Dolutegravir Possible When This Drug Is Used in First-Line Therapy?

by Thibault Mesplède and Mark A. Wainberg

Viruses 2014, 6(9), 3377-3385; https://doi.org/10.3390/v6093377 - 27 Aug 2014

Cited by 30 | Viewed by 7053

Abstract

Dolutegravir (DTG) is an HIV integrase inhibitor that was recently approved for therapy by the Food and Drug Administration in the United States. When used as part of first-line therapy, DTG is the only HIV drug that has not selected for resistance mutations [...] Read more.

Dolutegravir (DTG) is an HIV integrase inhibitor that was recently approved for therapy by the Food and Drug Administration in the United States. When used as part of first-line therapy, DTG is the only HIV drug that has not selected for resistance mutations in the clinic. We believe that this is due to the long binding time of DTG to the integrase enzyme as well as greatly diminished replication capacity on the part of viruses that might become resistant to DTG. We further speculate that DTG might be able to be used in strategies aimed at HIV eradication. Full article

(This article belongs to the Special Issue HIV Drug Resistance)

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Viruses, Volume 6, Issue 9 (September 2014) – 21 articles , Pages 3377-3698

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