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Viruses, Volume 6, Issue 10 (October 2014) , Pages 3699-4139

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Open AccessReview Current Perspectives on HIV-1 Antiretroviral Drug Resistance
Viruses 2014, 6(10), 4095-4139; https://doi.org/10.3390/v6104095
Received: 28 July 2014 / Revised: 8 October 2014 / Accepted: 20 October 2014 / Published: 24 October 2014
Cited by 56 | Viewed by 4758 | PDF Full-text (913 KB) | HTML Full-text | XML Full-text
Abstract
Current advancements in antiretroviral therapy (ART) have turned HIV-1 infection into a chronic and manageable disease. However, treatment is only effective until HIV-1 develops resistance against the administered drugs. The most recent antiretroviral drugs have become superior at delaying the evolution of acquired [...] Read more.
Current advancements in antiretroviral therapy (ART) have turned HIV-1 infection into a chronic and manageable disease. However, treatment is only effective until HIV-1 develops resistance against the administered drugs. The most recent antiretroviral drugs have become superior at delaying the evolution of acquired drug resistance. In this review, the viral fitness and its correlation to HIV-1 mutation rates and drug resistance are discussed while emphasizing the concept of lethal mutagenesis as an alternative therapy. The development of resistance to the different classes of approved drugs and the importance of monitoring antiretroviral drug resistance are also summarized briefly. Full article
(This article belongs to the Special Issue HIV Drug Resistance)
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Open AccessReview The Lysine 65 Residue in HIV-1 Reverse Transcriptase Function and in Nucleoside Analog Drug Resistance
Viruses 2014, 6(10), 4080-4094; https://doi.org/10.3390/v6104080
Received: 13 August 2014 / Revised: 19 October 2014 / Accepted: 20 October 2014 / Published: 23 October 2014
Cited by 8 | Viewed by 2325 | PDF Full-text (520 KB) | HTML Full-text | XML Full-text
Abstract
Mutations in HIV-1 reverse transcriptase (RT) that confer nucleoside analog RT inhibitor resistance have highlighted the functional importance of several active site residues (M184, Q151 and K65) in RT catalytic function. Of these, K65 residue is notable due to its pivotal position in [...] Read more.
Mutations in HIV-1 reverse transcriptase (RT) that confer nucleoside analog RT inhibitor resistance have highlighted the functional importance of several active site residues (M184, Q151 and K65) in RT catalytic function. Of these, K65 residue is notable due to its pivotal position in the dNTP-binding pocket, its involvement in nucleoside analog resistance and polymerase fidelity. This review focuses on K65 residue and summarizes a substantial body of biochemical and structural studies of its role in RT function and the functional consequences of the K65R mutation. Full article
(This article belongs to the Special Issue HIV Drug Resistance)
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Open AccessReview Human Viruses and Cancer
Viruses 2014, 6(10), 4047-4079; https://doi.org/10.3390/v6104047
Received: 1 August 2014 / Revised: 18 September 2014 / Accepted: 13 October 2014 / Published: 23 October 2014
Cited by 39 | Viewed by 5237 | PDF Full-text (1412 KB) | HTML Full-text | XML Full-text
Abstract
The first human tumor virus was discovered in the middle of the last century by Anthony Epstein, Bert Achong and Yvonne Barr in African pediatric patients with Burkitt’s lymphoma. To date, seven viruses -EBV, KSHV, high-risk HPV, MCPV, HBV, HCV and HTLV1- have [...] Read more.
The first human tumor virus was discovered in the middle of the last century by Anthony Epstein, Bert Achong and Yvonne Barr in African pediatric patients with Burkitt’s lymphoma. To date, seven viruses -EBV, KSHV, high-risk HPV, MCPV, HBV, HCV and HTLV1- have been consistently linked to different types of human cancer, and infections are estimated to account for up to 20% of all cancer cases worldwide. Viral oncogenic mechanisms generally include: generation of genomic instability, increase in the rate of cell proliferation, resistance to apoptosis, alterations in DNA repair mechanisms and cell polarity changes, which often coexist with evasion mechanisms of the antiviral immune response. Viral agents also indirectly contribute to the development of cancer mainly through immunosuppression or chronic inflammation, but also through chronic antigenic stimulation. There is also evidence that viruses can modulate the malignant properties of an established tumor. In the present work, causation criteria for viruses and cancer will be described, as well as the viral agents that comply with these criteria in human tumors, their epidemiological and biological characteristics, the molecular mechanisms by which they induce cellular transformation and their associated cancers. Full article
(This article belongs to the Special Issue Tumour Viruses) Printed Edition available
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Open AccessReview Interaction of KSHV with Host Cell Surface Receptors and Cell Entry
Viruses 2014, 6(10), 4024-4046; https://doi.org/10.3390/v6104024
Received: 17 August 2014 / Revised: 19 October 2014 / Accepted: 21 October 2014 / Published: 23 October 2014
Cited by 30 | Viewed by 3056 | PDF Full-text (801 KB) | HTML Full-text | XML Full-text
Abstract
Virus entry is a complex process characterized by a sequence of events. Since the discovery of KSHV in 1994, tremendous progress has been made in our understanding of KSHV entry into its in vitro target cells. KSHV entry is a complex multistep process [...] Read more.
Virus entry is a complex process characterized by a sequence of events. Since the discovery of KSHV in 1994, tremendous progress has been made in our understanding of KSHV entry into its in vitro target cells. KSHV entry is a complex multistep process involving viral envelope glycoproteins and several cell surface molecules that is utilized by KSHV for its attachment and entry. KSHV has a broad cell tropism and the attachment and receptor engagement on target cells have an important role in determining the cell type-specific mode of entry. KSHV utilizes heparan sulfate, integrins and EphrinA2 molecules as receptors which results in the activation of host cell pre-existing signal pathways that facilitate the subsequent cascade of events resulting in the rapid entry of virus particles, trafficking towards the nucleus followed by viral and host gene expression. KSHV enters human fibroblast cells by dynamin dependant clathrin mediated endocytosis and by dynamin independent macropinocytosis in dermal endothelial cells. Once internalized into endosomes, fusion of the viral envelope with the endosomal membranes in an acidification dependent manner results in the release of capsids which subsequently reaches the nuclear pore vicinity leading to the delivery of viral DNA into the nucleus. In this review, we discuss the principal mechanisms that enable KSHV to interact with the host cell surface receptors as well as the mechanisms that are required to modulate cell signaling machinery for a successful entry. Full article
(This article belongs to the Special Issue Kaposi's Sarcoma-Associated Herpesvirus) Printed Edition available
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Open AccessArticle KSHV miRNAs Decrease Expression of Lytic Genes in Latently Infected PEL and Endothelial Cells by Targeting Host Transcription Factors
Viruses 2014, 6(10), 4005-4023; https://doi.org/10.3390/v6104005
Received: 9 September 2014 / Revised: 17 October 2014 / Accepted: 21 October 2014 / Published: 23 October 2014
Cited by 25 | Viewed by 2618 | PDF Full-text (905 KB) | HTML Full-text | XML Full-text
Abstract
Kaposi’s sarcoma-associated herpesvirus (KSHV) microRNAs are encoded in the latency-associated region. Knockdown of KSHV miR-K12-3 and miR-K12-11 increased expression of lytic genes in BC-3 cells, and increased virus production from latently infected BCBL-1 cells. Furthermore, iSLK cells infected with miR-K12-3 and miR-K12-11 deletion [...] Read more.
Kaposi’s sarcoma-associated herpesvirus (KSHV) microRNAs are encoded in the latency-associated region. Knockdown of KSHV miR-K12-3 and miR-K12-11 increased expression of lytic genes in BC-3 cells, and increased virus production from latently infected BCBL-1 cells. Furthermore, iSLK cells infected with miR-K12-3 and miR-K12-11 deletion mutant viruses displayed increased spontaneous reactivation and were more sensitive to inducers of reactivation than cells infected with wild type KSHV. Predicted binding sites for miR-K12-3 and miR-K12-11 were found in the 3’UTRs of the cellular transcription factors MYB, Ets-1, and C/EBPα, which activate RTA, the KSHV replication and transcription activator. Targeting of MYB by miR-K12-11 was confirmed by cloning the MYB 3’UTR downstream from the luciferase reporter. Knockdown of miR‑K12-11 resulted in increased levels of MYB transcript, and knockdown of miR-K12-3 increased both C/EBPα and Ets-1 transcripts. Thus, miR-K12-11 and miR-K12-3 contribute to maintenance of latency by decreasing RTA expression indirectly, presumably via down‑regulation of MYB, C/EBPα and Ets-1, and possibly other host transcription factors. Full article
(This article belongs to the Special Issue Kaposi's Sarcoma-Associated Herpesvirus) Printed Edition available
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Open AccessReview Arboviral Bottlenecks and Challenges to Maintaining Diversity and Fitness during Mosquito Transmission
Viruses 2014, 6(10), 3991-4004; https://doi.org/10.3390/v6103991
Received: 22 September 2014 / Revised: 18 October 2014 / Accepted: 20 October 2014 / Published: 23 October 2014
Cited by 30 | Viewed by 3050 | PDF Full-text (277 KB) | HTML Full-text | XML Full-text | Correction
Abstract
The term arbovirus denotes viruses that are transmitted by arthropods, such as ticks, mosquitoes, and other biting arthropods. The infection of these vectors produces a certain set of evolutionary pressures on the virus; involving migration from the midgut, where the blood meal containing [...] Read more.
The term arbovirus denotes viruses that are transmitted by arthropods, such as ticks, mosquitoes, and other biting arthropods. The infection of these vectors produces a certain set of evolutionary pressures on the virus; involving migration from the midgut, where the blood meal containing the virus is processed, to the salivary glands, in order to transmit the virus to the next host. During this process the virus is subject to numerous bottlenecks, stochastic events that significantly reduce the number of viral particles that are able to infect the next stage. This article reviews the latest research on the bottlenecks that occur in arboviruses and the way in which these affect the evolution and fitness of these viruses. In particular we focus on the latest research on three important arboviruses, West Nile virus, Venezuelan equine encephalitis virus and Chikungunya viruses and compare the differing effects of the mosquito bottlenecks on these viruses as well as other evolutionary pressures that affect their evolution and transmission. Full article
(This article belongs to the Special Issue Interactions between Arboviruses and Arthropod Vectors)
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Open AccessReview Challenges in the Design of a T Cell Vaccine in the Context of HIV-1 Diversity
Viruses 2014, 6(10), 3968-3990; https://doi.org/10.3390/v6103968
Received: 31 July 2014 / Revised: 15 October 2014 / Accepted: 18 October 2014 / Published: 23 October 2014
Cited by 13 | Viewed by 2898 | PDF Full-text (566 KB) | HTML Full-text | XML Full-text
Abstract
The extraordinary variability of HIV-1 poses a major obstacle to vaccine development. The effectiveness of a vaccine is likely to vary dramatically in different populations infected with different HIV-1 subtypes, unless innovative vaccine immunogens are developed to protect against the range of HIV-1 [...] Read more.
The extraordinary variability of HIV-1 poses a major obstacle to vaccine development. The effectiveness of a vaccine is likely to vary dramatically in different populations infected with different HIV-1 subtypes, unless innovative vaccine immunogens are developed to protect against the range of HIV-1 diversity. Immunogen design for stimulating neutralizing antibody responses focuses on “breadth” – the targeting of a handful of highly conserved neutralizing determinants on the HIV-1 Envelope protein that can recognize the majority of viruses across all HIV-1 subtypes. An effective vaccine will likely require the generation of both broadly cross-neutralizing antibodies and non-neutralizing antibodies, as well as broadly cross-reactive T cells. Several approaches have been taken to design such broadly-reactive and cross-protective T cell immunogens. Artificial sequences have been designed that reduce the genetic distance between a vaccine strain and contemporary circulating viruses; “mosaic” immunogens extend this concept to contain multiple potential T cell epitope (PTE) variants; and further efforts attempt to focus T cell immunity on highly conserved regions of the HIV-1 genome. Thus far, a number of pre-clinical and early clinical studies have been performed assessing these new immunogens. In this review, the potential use of these new immunogens is explored. Full article
(This article belongs to the Special Issue AIDS Vaccine 2014)
Open AccessArticle Identification of FactorsInfluencing the Puumala Virus Seroprevalence within Its Reservoir in aMontane Forest Environment
Viruses 2014, 6(10), 3944-3967; https://doi.org/10.3390/v6103944
Received: 20 May 2014 / Revised: 3 September 2014 / Accepted: 29 September 2014 / Published: 23 October 2014
Cited by 4 | Viewed by 2167 | PDF Full-text (871 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Puumala virus (PUUV) is a major cause of mild to moderate haemorrhagic fever with renal syndrome and is transmitted by the bank vole (Myodes glareolus). There has been a high cumulative incidence of recorded human cases in South-eastern Germany since 2004 [...] Read more.
Puumala virus (PUUV) is a major cause of mild to moderate haemorrhagic fever with renal syndrome and is transmitted by the bank vole (Myodes glareolus). There has been a high cumulative incidence of recorded human cases in South-eastern Germany since 2004 when the region was first recognized as being endemic for PUUV. As the area is well known for outdoor recreation and the Bavarian Forest National Park (BFNP) is located in the region, the increasing numbers of recorded cases are of concern. To understand the population and environmental effects on the seroprevalence of PUUV in bank voles we trapped small mammals at 23 sites along an elevation gradient from 317 to 1420m above sea level. Generalized linear mixed effects models(GLMEM) were used to explore associations between the seroprevalence of PUUV in bank voles and climate and biotic factors. We found that the seroprevalence of PUUV was low (6%–7%) in 2008 and 2009, and reached 29% in 2010. PUUV seroprevalence was positively associated with the local species diversity and deadwood layer, and negatively associated with mean annual temperature, mean annual solar radiation, and herb layer. Based on these findings, an illustrative risk map for PUUV seroprevalence prediction in bank voles was created for an area of the national park. The map will help when planning infrastructure in the national park (e.g., huts, shelters, and trails). Full article
(This article belongs to the Special Issue Hantaviruses)
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Open AccessReview Regulation of HTLV-1 Tax Stability, Cellular Trafficking and NF-κB Activation by the Ubiquitin-Proteasome Pathway
Viruses 2014, 6(10), 3925-3943; https://doi.org/10.3390/v6103925
Received: 9 September 2014 / Revised: 15 October 2014 / Accepted: 21 October 2014 / Published: 23 October 2014
Cited by 14 | Viewed by 2778 | PDF Full-text (1178 KB) | HTML Full-text | XML Full-text
Abstract
Human T-cell leukemia virus type 1 (HTLV-1) is a complex retrovirus that infects CD4+ T cells and causes adult T-cell leukemia/lymphoma (ATLL) in 3%–5% of infected individuals after a long latent period. HTLV-1 Tax is a trans-activating protein that regulates viral gene [...] Read more.
Human T-cell leukemia virus type 1 (HTLV-1) is a complex retrovirus that infects CD4+ T cells and causes adult T-cell leukemia/lymphoma (ATLL) in 3%–5% of infected individuals after a long latent period. HTLV-1 Tax is a trans-activating protein that regulates viral gene expression and also modulates cellular signaling pathways to enhance T-cell proliferation and cell survival. The Tax oncoprotein promotes T-cell transformation, in part via constitutive activation of the NF-κB transcription factor; however, the underlying mechanisms remain unknown. Ubiquitination is a type of post-translational modification that occurs in a three-step enzymatic cascade mediated by E1, E2 and E3 enzymes and regulates protein stability as well as signal transduction, protein trafficking and the DNA damage response. Emerging studies indicate that Tax hijacks the ubiquitin machinery to activate ubiquitin-dependent kinases and downstream NF-κB signaling. Tax interacts with the E2 conjugating enzyme Ubc13 and is conjugated on C-terminal lysine residues with lysine 63-linked polyubiquitin chains. Tax K63-linked polyubiquitination may serve as a platform for signaling complexes since this modification is critical for interactions with NEMO and IKK. In addition to NF-κB signaling, mono- and polyubiquitination of Tax also regulate its subcellular trafficking and stability. Here, we review recent advances in the diverse roles of ubiquitin in Tax function and how Tax usurps the ubiquitin-proteasome pathway to promote oncogenesis. Full article
(This article belongs to the Special Issue Viruses and the Ubiquitin/Proteasome System)
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Open AccessReview Protein Folding Activity of the Ribosome (PFAR) –– A Target for Antiprion Compounds
Viruses 2014, 6(10), 3907-3924; https://doi.org/10.3390/v6103907
Received: 15 August 2014 / Revised: 13 October 2014 / Accepted: 15 October 2014 / Published: 23 October 2014
Cited by 9 | Viewed by 2542 | PDF Full-text (1067 KB) | HTML Full-text | XML Full-text
Abstract
Prion diseases are fatal neurodegenerative diseases affecting mammals. Prions are misfolded amyloid aggregates of the prion protein (PrP), which form when the alpha helical, soluble form of PrP converts to an aggregation-prone, beta sheet form. Thus, prions originate as protein folding problems. The [...] Read more.
Prion diseases are fatal neurodegenerative diseases affecting mammals. Prions are misfolded amyloid aggregates of the prion protein (PrP), which form when the alpha helical, soluble form of PrP converts to an aggregation-prone, beta sheet form. Thus, prions originate as protein folding problems. The discovery of yeast prion(s) and the development of a red-/white-colony based assay facilitated safe and high-throughput screening of antiprion compounds. With this assay three antiprion compounds; 6-aminophenanthridine (6AP), guanabenz acetate (GA), and imiquimod (IQ) have been identified. Biochemical and genetic studies reveal that these compounds target ribosomal RNA (rRNA) and inhibit specifically the protein folding activity of the ribosome (PFAR). The domain V of the 23S/25S/28S rRNA of the large ribosomal subunit constitutes the active site for PFAR. 6AP and GA inhibit PFAR by competition with the protein substrates for the common binding sites on the domain V rRNA. PFAR inhibition by these antiprion compounds opens up new possibilities for understanding prion formation, propagation and the role of the ribosome therein. In this review, we summarize and analyze the correlation between PFAR and prion processes using the antiprion compounds as tools. Full article
(This article belongs to the Special Issue Recent Developments in the Prion Field)
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Open AccessArticle Development and Validation of a Multiplex Reverse Transcription PCR Assay for Simultaneous Detection of Three Papaya Viruses
Viruses 2014, 6(10), 3893-3906; https://doi.org/10.3390/v6103893
Received: 6 August 2014 / Revised: 13 October 2014 / Accepted: 13 October 2014 / Published: 21 October 2014
Cited by 7 | Viewed by 2934 | PDF Full-text (880 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Papaya ringspot virus (PRSV), Papaya leaf distortion mosaic virus (PLDMV), and Papaya mosaic virus (PapMV) produce similar symptoms in papaya. Each threatens commercial production of papaya on Hainan Island, China. In this study, a multiplex reverse transcription PCR assay was developed to detect [...] Read more.
Papaya ringspot virus (PRSV), Papaya leaf distortion mosaic virus (PLDMV), and Papaya mosaic virus (PapMV) produce similar symptoms in papaya. Each threatens commercial production of papaya on Hainan Island, China. In this study, a multiplex reverse transcription PCR assay was developed to detect simultaneously these three viruses by screening combinations of mixed primer pairs and optimizing the multiplex RT-PCR reaction conditions. A mixture of three specific primer pairs was used to amplify three distinct fragments of 613 bp from the P3 gene of PRSV, 355 bp from the CP gene of PLDMV, and 205 bp from the CP gene of PapMV, demonstrating the assay’s specificity. The sensitivity of the multiplex RT-PCR was evaluated by showing plasmids containing each of the viral target genes with 1.44 × 103, 1.79 × 103, and 1.91 × 102 copies for the three viruses could be detected successfully. The multiplex RT-PCR was applied successfully for detection of three viruses from 341 field samples collected from 18 counties of Hainan Island, China. Rates of single infections were 186/341 (54.5%), 93/341 (27.3%), and 3/341 (0.9%), for PRSV, PLDMV, and PapMV, respectively; 59/341 (17.3%) of the samples were co-infected with PRSV and PLDMV, which is the first time being reported in Hainan Island. This multiplex RT-PCR assay is a simple, rapid, sensitive, and cost-effective method for detecting multiple viruses in papaya and can be used for routine molecular diagnosis and epidemiological studies in papaya. Full article
(This article belongs to the Section Viruses of Plants, Fungi and Protozoa)
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Open AccessReview The Structure of Human Prions: From Biology to Structural Models—Considerations and Pitfalls
Viruses 2014, 6(10), 3875-3892; https://doi.org/10.3390/v6103875
Received: 27 August 2014 / Revised: 14 October 2014 / Accepted: 15 October 2014 / Published: 20 October 2014
Cited by 6 | Viewed by 3788 | PDF Full-text (606 KB) | HTML Full-text | XML Full-text
Abstract
The Structure of Human Prions: From Biology to Structural Models — Considerations and Pitfalls Full article
(This article belongs to the Special Issue Recent Developments in the Prion Field)
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Open AccessEditorial Remembering Professor Walter A. Scott
Viruses 2014, 6(10), 3873-3874; https://doi.org/10.3390/v6103873
Received: 9 October 2014 / Accepted: 14 October 2014 / Published: 20 October 2014
Viewed by 1541 | PDF Full-text (236 KB) | HTML Full-text | XML Full-text
Abstract
Walter Scott was a Biochemistry professor at the University of Miami, Miller School of Medicine and a leading figure in the field of HIV drug resistance. His untimely passing in January 2013 marked a loss for his family, as well as for students [...] Read more.
Walter Scott was a Biochemistry professor at the University of Miami, Miller School of Medicine and a leading figure in the field of HIV drug resistance. His untimely passing in January 2013 marked a loss for his family, as well as for students and colleagues who knew him as a dedicated and unassuming scholar, and a lively scientist with a great sense of humor. Full article
(This article belongs to the Special Issue HIV Drug Resistance)
Open AccessReview Impact of Human Immunodeficiency Virus Type-1 Sequence Diversity on Antiretroviral Therapy Outcomes
Viruses 2014, 6(10), 3855-3872; https://doi.org/10.3390/v6103855
Received: 17 July 2014 / Revised: 9 October 2014 / Accepted: 13 October 2014 / Published: 20 October 2014
Cited by 9 | Viewed by 2169 | PDF Full-text (453 KB) | HTML Full-text | XML Full-text
Abstract
Worldwide circulating HIV-1 genomes show extensive variation represented by different subtypes, polymorphisms and drug-resistant strains. Reports on the impact of sequence variation on antiretroviral therapy (ART) outcomes are mixed. In this review, we summarize relevant published data from both resource-rich and resource-limited countries [...] Read more.
Worldwide circulating HIV-1 genomes show extensive variation represented by different subtypes, polymorphisms and drug-resistant strains. Reports on the impact of sequence variation on antiretroviral therapy (ART) outcomes are mixed. In this review, we summarize relevant published data from both resource-rich and resource-limited countries in the last 10 years on the impact of HIV-1 sequence diversity on treatment outcomes. The prevalence of transmission of drug resistant mutations (DRMs) varies considerably, ranging from 0% to 27% worldwide. Factors such as geographic location, access and availability to ART, duration since inception of treatment programs, quality of care, risk-taking behaviors, mode of transmission, and viral subtype all dictate the prevalence in a particular geographical region. Although HIV-1 subtype may not be a good predictor of treatment outcome, review of emerging evidence supports the fact that HIV-1 genome sequence-resulting from natural polymorphisms or drug-associated mutations-matters when it comes to treatment outcomes. Therefore, continued surveillance of drug resistant variants in both treatment-naïve and treatment-experienced populations is needed to reduce the transmission of DRMs and to optimize the efficacy of the current ART armamentarium. Full article
(This article belongs to the Special Issue HIV Drug Resistance)
Open AccessArticle A Loop Region in the N-Terminal Domain of Ebola Virus VP40 Is Important in Viral Assembly, Budding, and Egress
Viruses 2014, 6(10), 3837-3854; https://doi.org/10.3390/v6103837
Received: 1 July 2014 / Revised: 9 October 2014 / Accepted: 11 October 2014 / Published: 17 October 2014
Cited by 18 | Viewed by 4839 | PDF Full-text (1623 KB) | HTML Full-text | XML Full-text
Abstract
Ebola virus (EBOV) causes viral hemorrhagic fever in humans and can have clinical fatality rates of ~60%. The EBOV genome consists of negative sense RNA that encodes seven proteins including viral protein 40 (VP40). VP40 is the major Ebola virus matrix protein and [...] Read more.
Ebola virus (EBOV) causes viral hemorrhagic fever in humans and can have clinical fatality rates of ~60%. The EBOV genome consists of negative sense RNA that encodes seven proteins including viral protein 40 (VP40). VP40 is the major Ebola virus matrix protein and regulates assembly and egress of infectious Ebola virus particles. It is well established that VP40 assembles on the inner leaflet of the plasma membrane of human cells to regulate viral budding where VP40 can produce virus like particles (VLPs) without other Ebola virus proteins present. The mechanistic details, however, of VP40 lipid-interactions and protein-protein interactions that are important for viral release remain to be elucidated. Here, we mutated a loop region in the N-terminal domain of VP40 (Lys127, Thr129, and Asn130) and find that mutations (K127A, T129A, and N130A) in this loop region reduce plasma membrane localization of VP40. Additionally, using total internal reflection fluorescence microscopy and number and brightness analysis we demonstrate these mutations greatly reduce VP40 oligomerization. Lastly, VLP assays demonstrate these mutations significantly reduce VLP release from cells. Taken together, these studies identify an important loop region in VP40 that may be essential to viral egress. Full article
(This article belongs to the collection Advances in Ebolavirus, Marburgvirus, and Cuevavirus Research)
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Open AccessShort Communication Spread of Oropouche Virus into the Central Nervous System in Mouse
Viruses 2014, 6(10), 3827-3836; https://doi.org/10.3390/v6103827
Received: 6 August 2014 / Revised: 23 September 2014 / Accepted: 24 September 2014 / Published: 10 October 2014
Cited by 7 | Viewed by 2598 | PDF Full-text (1100 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Oropouche virus (OROV) is an important cause of arboviral illness in Brazil and other Latin American countries, with most cases clinically manifested as acute febrile illness referred to as Oropouche fever, including myalgia, headache, arthralgia and malaise. However, OROV can also affect the [...] Read more.
Oropouche virus (OROV) is an important cause of arboviral illness in Brazil and other Latin American countries, with most cases clinically manifested as acute febrile illness referred to as Oropouche fever, including myalgia, headache, arthralgia and malaise. However, OROV can also affect the central nervous system (CNS) with clinical neurological implications. Little is known regarding OROV pathogenesis, especially how OROV gains access to the CNS. In the present study, neonatal BALB/c mice were inoculated with OROV by the subcutaneous route and the progression of OROV spread into the CNS was evaluated. Immunohistochemistry revealed that OROV infection advances from posterior parts of the brain, including the periaqueductal gray, toward the forebrain. In the early phases of the infection OROV gains access to neural routes, reaching the spinal cord and ascending to the brain through brainstem regions, with little inflammation. Later, as infection progresses, OROV crosses the blood-brain barrier, resulting in more intense spread into the brain parenchyma, with more severe manifestations of encephalitis. Full article
(This article belongs to the Section Animal Viruses)
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Open AccessReview Influenza Vaccines: A Moving Interdisciplinary Field
Viruses 2014, 6(10), 3809-3826; https://doi.org/10.3390/v6103809
Received: 31 July 2014 / Revised: 1 October 2014 / Accepted: 2 October 2014 / Published: 9 October 2014
Cited by 10 | Viewed by 5445 | PDF Full-text (486 KB) | HTML Full-text | XML Full-text
Abstract
Vaccination is by far the most effective way of preventing morbidity and mortality due to infection of the upper respiratory tract by influenza virus. Current vaccines require yearly vaccine updates as the influenza virus can escape vaccine-induced humoral immunity due to the antigenic [...] Read more.
Vaccination is by far the most effective way of preventing morbidity and mortality due to infection of the upper respiratory tract by influenza virus. Current vaccines require yearly vaccine updates as the influenza virus can escape vaccine-induced humoral immunity due to the antigenic variability of its surface antigens. In case of a pandemic, new vaccines become available too late with current vaccine practices. New technologies that allow faster production of vaccine seed strains in combination with alternative production platforms and vaccine formulations may shorten the time gap between emergence of a new influenza virus and a vaccine becoming available. Adjuvants may allow antigen-sparing, allowing more people to be vaccinated with current vaccine production capacity. Adjuvants and universal vaccines can target immune responses to more conserved influenza epitopes, which eventually will result in broader protection for a longer time. In addition, further immunological studies are needed to gain insights in the immune features that contribute to protection from influenza-related disease and mortality, allowing redefinition of correlates of protection beyond virus neutralization in vitro. Full article
Open AccessReview From Crescent to Mature Virion: Vaccinia Virus Assembly and Maturation
Viruses 2014, 6(10), 3787-3808; https://doi.org/10.3390/v6103787
Received: 2 September 2014 / Revised: 29 September 2014 / Accepted: 2 October 2014 / Published: 7 October 2014
Cited by 9 | Viewed by 3557 | PDF Full-text (560 KB) | HTML Full-text | XML Full-text
Abstract
Vaccinia virus (VACV) has achieved unprecedented success as a live viral vaccine for smallpox which mitigated eradication of the disease. Vaccinia virus has a complex virion morphology and recent advances have been made to answer some of the key outstanding questions, in particular, [...] Read more.
Vaccinia virus (VACV) has achieved unprecedented success as a live viral vaccine for smallpox which mitigated eradication of the disease. Vaccinia virus has a complex virion morphology and recent advances have been made to answer some of the key outstanding questions, in particular, the origin and biogenesis of the virion membrane, the transformation from immature virion (IV) to mature virus (MV), and the role of several novel genes, which were previously uncharacterized, but have now been shown to be essential for VACV virion formation. This new knowledge will undoubtedly contribute to the rational design of safe, immunogenic vaccine candidates, or effective antivirals in the future. This review endeavors to provide an update on our current knowledge of the VACV maturation processes with a specific focus on the initiation of VACV replication through to the formation of mature virions. Full article
(This article belongs to the Special Issue Virus Maturation)
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Open AccessArticle Effect of Bacteriophage Infection in Combination with Tobramycin on the Emergence of Resistance in Escherichia coli and Pseudomonas aeruginosa Biofilms
Viruses 2014, 6(10), 3778-3786; https://doi.org/10.3390/v6103778
Received: 20 August 2014 / Revised: 26 September 2014 / Accepted: 26 September 2014 / Published: 3 October 2014
Cited by 24 | Viewed by 3805 | PDF Full-text (239 KB) | HTML Full-text | XML Full-text
Abstract
Bacteriophage infection and antibiotics used individually to reduce biofilm mass often result in the emergence of significant levels of phage and antibiotic resistant cells. In contrast, combination therapy in Escherichia coli biofilms employing T4 phage and tobramycin resulted in greater than 99% and [...] Read more.
Bacteriophage infection and antibiotics used individually to reduce biofilm mass often result in the emergence of significant levels of phage and antibiotic resistant cells. In contrast, combination therapy in Escherichia coli biofilms employing T4 phage and tobramycin resulted in greater than 99% and 39% reduction in antibiotic and phage resistant cells, respectively. In P. aeruginosa biofilms, combination therapy resulted in a 60% and 99% reduction in antibiotic and PB-1 phage resistant cells, respectively. Although the combined treatment resulted in greater reduction of E. coli CFUs compared to the use of antibiotic alone, infection of P. aeruginosa biofilms with PB-1 in the presence of tobramycin was only as effective in the reduction of CFUs as the use of antibiotic alone. The study demonstrated phage infection in combination with tobramycin can significantly reduce the emergence of antibiotic and phage resistant cells in both E. coli and P. aeruginosa biofilms, however, a reduction in biomass was dependent on the phage-host system. Full article
(This article belongs to the Section Bacterial Viruses)
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Open AccessArticle Molecular Modeling of Prion Transmission to Humans
Viruses 2014, 6(10), 3766-3777; https://doi.org/10.3390/v6103766
Received: 24 July 2014 / Revised: 26 September 2014 / Accepted: 30 September 2014 / Published: 2 October 2014
Cited by 4 | Viewed by 2941 | PDF Full-text (313 KB) | HTML Full-text | XML Full-text
Abstract
Using different prion strains, such as the variant Creutzfeldt-Jakob disease agent and the atypical bovine spongiform encephalopathy agents, and using transgenic mice expressing human or bovine prion protein, we assessed the reliability of protein misfolding cyclic amplification (PMCA) to model interspecies and genetic [...] Read more.
Using different prion strains, such as the variant Creutzfeldt-Jakob disease agent and the atypical bovine spongiform encephalopathy agents, and using transgenic mice expressing human or bovine prion protein, we assessed the reliability of protein misfolding cyclic amplification (PMCA) to model interspecies and genetic barriers to prion transmission. We compared our PMCA results with in vivo transmission data characterized by attack rates, i.e., the percentage of inoculated mice that developed the disease. Using 19 seed/substrate combinations, we observed that a significant PMCA amplification was only obtained when the mouse line used as substrate is susceptible to the corresponding strain. Our results suggest that PMCA provides a useful tool to study genetic barriers to transmission and to study the zoonotic potential of emerging prion strains. Full article
(This article belongs to the Special Issue Recent Developments in the Prion Field)
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Open AccessArticle Mutation of the Highly Conserved Ser-40 of the HIV-1 p6 Gag Protein to Phe Causes the Formation of a Hydrophobic Patch, Enhances Membrane Association, and Polyubiquitination of Gag
Viruses 2014, 6(10), 3738-3765; https://doi.org/10.3390/v6103738
Received: 6 August 2014 / Revised: 19 September 2014 / Accepted: 26 September 2014 / Published: 2 October 2014
Cited by 6 | Viewed by 3619 | PDF Full-text (1237 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The HIV-1 p6 Gag protein contains two late assembly (l-) domains that recruit proteins of the endosomal sorting complex required for transport (ESCRT) pathway to mediate membrane fission between the nascent virion and the cell membrane. It was recently demonstrated that mutation of [...] Read more.
The HIV-1 p6 Gag protein contains two late assembly (l-) domains that recruit proteins of the endosomal sorting complex required for transport (ESCRT) pathway to mediate membrane fission between the nascent virion and the cell membrane. It was recently demonstrated that mutation of the highly conserved Ser-40 to Phe (S40F) disturbs CA-SP1 processing, virus morphogenesis, and infectivity. It also causes the formation of filopodia-like structures, while virus release remains unaffected. Here, we show that the mutation S40F, but not the conservative mutation to Asp (S40D) or Asn (S40N), augments membrane association, K48-linked polyubiquitination, entry into the 26S proteasome, and, consequently, enhances MHC-I antigen presentation of Gag derived epitopes. Nuclear magnetic resonance (NMR) structure analyses revealed that the newly introduced Phe-40, together with Tyr-36, causes the formation of a hydrophobic patch at the C-terminal α-helix of p6, providing a molecular rationale for the enhanced membrane association of Gag observed in vitro and in HIV-1 expressing cells. The extended exposure of the S40F mutant to unidentified membrane-resident ubiquitin E3-ligases might trigger the polyubiquitination of Gag. The cumulative data support a previous model of a so far undefined property of p6, which, in addition to MA, acts as membrane targeting domain of Gag. Full article
(This article belongs to the Special Issue Virus Maturation)
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Open AccessReview Prion Protein-Specific Antibodies-Development, Modes of Action and Therapeutics Application
Viruses 2014, 6(10), 3719-3737; https://doi.org/10.3390/v6103719
Received: 31 July 2014 / Revised: 22 September 2014 / Accepted: 23 September 2014 / Published: 1 October 2014
Cited by 8 | Viewed by 3771 | PDF Full-text (641 KB) | HTML Full-text | XML Full-text
Abstract
Prion diseases or Transmissible Spongiform Encephalopathies (TSEs) are lethal neurodegenerative disorders involving the misfolding of the host encoded cellular prion protein, PrPC. This physiological form of the protein is expressed throughout the body, and it reaches the highest levels in the [...] Read more.
Prion diseases or Transmissible Spongiform Encephalopathies (TSEs) are lethal neurodegenerative disorders involving the misfolding of the host encoded cellular prion protein, PrPC. This physiological form of the protein is expressed throughout the body, and it reaches the highest levels in the central nervous system where the pathology occurs. The conversion into the pathogenic isoform denoted as prion or PrPSc is the key event in prion disorders. Prominent candidates for the treatment of prion diseases are antibodies and their derivatives. Anti-PrPC antibodies are able to clear PrPSc from cell culture of infected cells. Furthermore, application of anti-PrPC antibodies suppresses prion replication in experimental animal models. Major drawbacks of immunotherapy are immune tolerance, the risks of neurotoxic side effects, limited ability of compounds to cross the blood-brain barrier and their unfavorable pharmacokinetic. The focus of this review is to recapitulate the current understanding of the molecular mechanisms for antibody mediated anti-prion activity. Although relevant for designing immunotherapeutic tools, the characterization of key antibody parameters shaping the molecular mechanism of the PrPC to PrPSc conversion remains elusive. Moreover, this review illustrates the various attempts towards the development of anti-PrP antibody compounds and discusses therapeutic candidates that modulate PrP expression. Full article
(This article belongs to the Special Issue Recent Developments in the Prion Field)
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Open AccessLetter A Call to Action to Enhance Filovirus Disease Outbreak Preparedness and Response
Viruses 2014, 6(10), 3699-3718; https://doi.org/10.3390/v6103699
Received: 8 September 2014 / Revised: 23 September 2014 / Accepted: 23 September 2014 / Published: 30 September 2014
Cited by 5 | Viewed by 5026 | PDF Full-text (860 KB) | HTML Full-text | XML Full-text
Abstract
The frequency and magnitude of recognized and declared filovirus-disease outbreaks have increased in recent years, while pathogenic filoviruses are potentially ubiquitous throughout sub-Saharan Africa. Meanwhile, the efficiency and effectiveness of filovirus-disease outbreak preparedness and response efforts are currently limited by inherent challenges and [...] Read more.
The frequency and magnitude of recognized and declared filovirus-disease outbreaks have increased in recent years, while pathogenic filoviruses are potentially ubiquitous throughout sub-Saharan Africa. Meanwhile, the efficiency and effectiveness of filovirus-disease outbreak preparedness and response efforts are currently limited by inherent challenges and persistent shortcomings. This paper delineates some of these challenges and shortcomings and provides a proposal for enhancing future filovirus-disease outbreak preparedness and response. The proposal serves as a call for prompt action by the organizations that comprise filovirus-disease outbreak response teams, namely, Ministries of Health of outbreak-prone countries, the World Health Organization, Médecins Sans Frontières, the Centers for Disease Control and Prevention—Atlanta, and others. Full article
(This article belongs to the collection Advances in Ebolavirus, Marburgvirus, and Cuevavirus Research)
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