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Sudhakar Agnihothram, Vineet D Menachery, Boyd L Yount, Lisa C Lindesmith, Trevor Scobey, Alan Whitmore, Alexandra Schäfer, Mark T Heise, Ralph S Baric
Zoonotic viruses circulate as swarms in animal reservoirs and can emerge into human populations causing epidemics that adversely affect public health. Portable, safe, and effective vaccine platforms are needed in the context of these outbreak and emergence situations. In this manuscript, we report the generation and characterization of an alphavirus replicon vaccine platform based on a non-select agent, attenuated Venezuelan equine encephalitis (VEE) virus vaccine strain 3526 (VRP 3526). Using both noroviruses and coronaviruses as model systems, we demonstrate utility of the VRP 3526 platform in generation of recombinant proteins, production of virus like particles, and in vivo efficacy as a vaccine against emergent viruses...
March 14, 2018: Journal of Virology
Marta Runowska, Dominik Majewski, Karolina Niklas, Mariusz Puszczewicz
Chikungunya virus (CHIKV) is an arthropod-borne alphavirus, transmitted by Aedes aegypti and Aedes albopictus mosquitoes. It is responsible for a febrile illness, typically accompanied by maculopapular rash and severe, incapacitating arthralgia. The disease, although generally self-limiting, frequently evolves into a long-lasting, debilitating rheumatic disorder, which shares many clinical features with rheumatoid arthritis (RA). The underlying mechanism by which CHIKV induces persistent arthritis remains under investigation, however, currently, attention is drawn to the fact, that chronic chikungunya (CHIK) and RA have many common cellular and cytokine pathways involved in their pathogenesis...
March 2, 2018: Clinical and Experimental Rheumatology
G E Chapman, M Baylis, D Archer, J M Daly
Equine populations worldwide are at increasing risk of infection by viruses transmitted by biting arthropods including mosquitoes, biting midges (Culicoides), sandflies and ticks. These include the flaviviruses (Japanese encephalitis, West Nile and Murray Valley encephalitis), alphaviruses (eastern, western and Venezuelan encephalitis) and the orbiviruses (African horse sickness and equine encephalosis). This review provides an overview of the challenges faced in the surveillance, prevention and control of the major equine arboviruses, particularly in the context of these viruses emerging in new regions of the world...
March 8, 2018: Equine Veterinary Journal
Camille Zambaz, Diana Dan
Arthritis and arthralgia during a viral infection are often polyarticular and symmetric and can mimic rheumatoid arthritis. Depending on germs, others signs and symptoms as fever, cutaneous rash (Parvovirus B19) or jaundice (hepatitis) can be present. Worldwide most common germs are Parvovirus B19, hepatitis B and C, HIV and alphavirus. There are significant differences throughout the world and epidemiology continues to evolve with a progression of vector-borne infections. Diagnosis of viral arthritis is often difficult and is based on epidemiological, clinical and serological data...
March 7, 2018: Revue Médicale Suisse
Benjamin Götte, Lifeng Liu, Gerald M McInerney
Alphaviruses encode 4 non-structural proteins (nsPs), most of which have well-understood functions in capping and membrane association (nsP1), polyprotein processing and RNA helicase activity (nsP2) and as RNA-dependent RNA polymerase (nsP4). The function of nsP3 has been more difficult to pin down and it has long been referred to as the more enigmatic of the nsPs. The protein comprises three domains, an N-terminal macro domain, a central zinc-binding domain and a C-terminal hypervariable domain (HVD). In this article, we review old and new literature about the functions of the three domains...
February 28, 2018: Viruses
P G Ferreira, A C Ferraz, J E Figueiredo, C F Lima, V G Rodrigues, A G Taranto, J M S Ferreira, G C Brandão, S A Vieira-Filho, L P Duarte, C L de Brito Magalhães, J C de Magalhães
Mayaro fever, caused by Mayaro virus (MAYV) is a sub-lethal disease with symptoms that are easily confused with those of dengue fever, except for polyarthralgia, which may culminate in physical incapacitation. Recently, outbreaks of MAYV have been documented in metropolitan areas, and to date, there is no therapy or vaccine available. Moreover, there is no information regarding the three-dimensional structure of the viral proteins of MAYV, which is important in the search for antivirals. In this work, we constructed a three-dimensional model of protein C of MAYV by homology modelling, and this was employed in a manner similar to that of receptors in virtual screening studies to evaluate 590 molecules as prospective antiviral agents...
February 24, 2018: Archives of Virology
Rebecca S Brown, Judy J Wan, Margaret Kielian
Alphaviruses are enveloped positive sense RNA viruses and include serious human pathogens, such as the encephalitic alphaviruses and Chikungunya virus. Alphaviruses are transmitted to humans primarily by mosquito vectors and include species that are classified as emerging pathogens. Alphaviruses assemble highly organized, spherical particles that bud from the plasma membrane. In this review, we discuss what is known about the alphavirus exit pathway during a cellular infection. We describe the viral protein interactions that are critical for virus assembly/budding and the host factors that are involved, and we highlight the recent discovery of cell-to-cell transmission of alphavirus particles via intercellular extensions...
February 22, 2018: Viruses
Margus Varjak, Isabelle Dietrich, Vattipally B Sreenu, Bethan Eluned Till, Andres Merits, Alain Kohl, Esther Schnettler
Mosquitoes transmit several human- and animal-pathogenic alphaviruses ( Togaviridae family). In alphavirus-infected mosquito cells two different types of virus-specific small RNAs are produced as part of the RNA interference response: short-interfering (si)RNAs and PIWI-interacting (pi)RNAs. The siRNA pathway is generally thought to be the main antiviral pathway. Although an antiviral activity has been suggested for the piRNA pathway its role in host defences is not clear. Knock down of key proteins of the piRNA pathway (Ago3 and Piwi5) in Aedes aegypti -derived cells reduced the production of alphavirus chikungunya virus (CHIKV)-specific piRNAs but had no effect on virus replication...
February 18, 2018: Viruses
Elisa X Y Lim, Aroon Supramaniam, Hayman Lui, Peta Coles, Wai Suet Lee, Xiang Liu, Penny A Rudd, Lara J Herrero
Arthritogenic alphavirus infections often result in debilitating musculoskeletal disorders that affect the joints, muscle, and bone. In order to evaluate the infection profile of primary human skeletal muscle and chondrocyte cells to Ross River virus (RRV) in vitro, cells were infected at a multiplicity of infection (MOI) of 1 over a period of two days. Viral titers were determined by plaque assay and cytokine expression by Bio-Plex® assays using the supernatants harvested. Gene expression studies were conducted using total RNA isolated from cells...
February 15, 2018: Viruses
Victoria K Baxter, Elizabeth M Troisi, Nathan M Pate, Julia N Zhao, Diane E Griffin
Central nervous system (CNS) infection of C57BL/6 mice with the TE strain of Sindbis virus (SINV) provides a valuable animal model for studying the pathogenesis of alphavirus encephalomyelitis. While SINV TE inoculated intracranially causes little mortality, 20-30 % of mice inoculated intranasally (IN) died 8 to 11 days after infection, the period during which immune cells typically infiltrate the brain and clear infectious virus. To examine the mechanism behind the mortality, mice infected IN with SINV TE were monitored for evidence of neurological disease, and those with signs of severe disease (moribund) were sacrificed and tissues collected...
February 1, 2018: Journal of General Virology
Cheng Hu, Ying Liu, Yuan Lin, Jian-Kai Liang, Wen-Wen Zhong, Ke Li, Wen-Tao Huang, De-Juan Wang, Guang-Mei Yan, Wen-Bo Zhu, Jian-Guang Qiu, Xin Gao
Muscle-invasive bladder cancer (MIBC) is associated with low survival and high recurrence rates even in cases in which patients receive systemic treatments, such as surgery and chemotherapy. Here, we found that a naturally existing alphavirus, namely, M1, selectively kills bladder cancer cells but not normal cells, findings supported by our observations of changes in viral replication and MIBC and patient-derived MIBC cell apoptosis. Transcriptome analysis revealed that interferon-stimulated genes (ISGs) are expressed at low levels in sensitive bladder cancer cells and high levels in resistant cells...
February 15, 2018: Cell Death & Disease
Kenneth Lundstrom
Oncolytic viruses have demonstrated selective replication and killing of tumor cells. Different types of oncolytic viruses - adenoviruses, alphaviruses, herpes simplex viruses, Newcastle disease viruses, rhabdoviruses, Coxsackie viruses, and vaccinia viruses - have been applied as either naturally occurring or engineered vectors. Numerous studies in animal-tumor models have demonstrated substantial tumor regression and prolonged survival rates. Moreover, clinical trials have confirmed good safety profiles and therapeutic efficacy for oncolytic viruses...
2018: Biologics: Targets & Therapy
Elisa X Y Lim, Wai Suet Lee, Eugene T Madzokere, Lara J Herrero
Alphaviruses are arthropod-borne viruses and are predominantly transmitted via mosquito vectors. This vector preference by alphaviruses raises the important question of the determinants that contribute to vector competence. There are several tissue barriers of the mosquito that the virus must overcome in order to establish a productive infection. Of importance are the midgut, basal lamina and the salivary glands. Infection of the salivary glands is crucial for virus transmission during the mosquito's subsequent bloodfeed...
February 14, 2018: Viruses
Thérèse Atieh, Miriam Diala El Ayoubi, Fabien Aubry, Stéphane Priet, Xavier de Lamballerie, Antoine Nougairède
Reverse genetics is key technology for producing wild-type and genetically modified viruses. The ISA (Infectious Subgenomic Amplicons) method is a recent versatile and user-friendly reverse genetics method to rescue RNA viruses. The main constraint of its canonic protocol was the requirement to produce (e.g., by DNA synthesis or fusion PCR) 5' and 3' modified genomic fragments encompassing the human cytomegalovirus promoter (pCMV) and the hepatitis delta virus ribozyme/simian virus 40 polyadenylation signal (HDR/SV40pA), respectively...
2018: PloS One
Syuhadaratul Aini Mohamat, Rafidah Hanim Shueb, Nor Fazila Che Mat
Chikungunya virus (CHIKV) is a re-emerging mosquito-borne alphavirus that poses a threat to human worldwide. Driven by the lack of approved medication and vaccination, research on anti-Chikungunya agents has received great attention. In an effort to determine potential inhibitor of CHIKV, this study aimed at investigating the potential anti-viral activity of Oroxylum indicum extracts towards CHIKV-infected Vero cells. The virucidal, pre- and post-treatment effects of O. indicum were evaluated, using the maximum non-toxic dose of O...
March 2018: Indian Journal of Microbiology
Farhana Abu Bakar, Lisa F P Ng
Alphaviruses are enveloped, positive single-stranded RNA viruses, typically transmitted by arthropods. They often cause arthralgia or encephalitic diseases in infected humans and there is currently no targeted antiviral treatment available. The re-emergence of alphaviruses in Asia, Europe, and the Americas over the last decade, including chikungunya and o'nyong'nyong viruses, have intensified the search for selective inhibitors. In this review, we highlight key molecular determinants within the alphavirus replication complex that have been identified as viral targets, focusing on their structure and functionality in viral dissemination...
February 9, 2018: Viruses
Luis Carrasco, Miguel Angel Sanz, Esther González-Almela
Sindbis virus (SINV) contains an RNA genome of positive polarity with two open reading frames (ORFs). The first ORF is translated from the genomic RNA (gRNA), rendering the viral non-structural proteins, whereas the second ORF is translated from a subgenomic mRNA (sgRNA), which directs the synthesis of viral structural proteins. SINV infection strongly inhibits host cell translation through a variety of different mechanisms, including the phosphorylation of the eukaryotic initiation factor eIF2α and the redistribution of cellular proteins from the nucleus to the cytoplasm...
February 8, 2018: Viruses
René Toribio, Irene Díaz-López, Jasminka Boskovic, Iván Ventoso
The topology and dynamics of the scanning ribosomal 43S pre-initiation complex (PIC) bound to mRNA and initiation factors (eIFs) are probably the least understood aspects of translation initiation in eukaryotes. Recently, we described a trapping mechanism in alphavirus that stalls the PIC during scanning of viral mRNA. Using this model, we were able to snapshot for the first time the eIF4A helicase bound to mRNA in a 48S initiation complex assembled in vitro. This interaction was only detected in the presence of the natural stem loop structure (DLP) located downstream from the AUG in viral mRNA that promoted stalling of the PIC, suggesting that DLP stability was enough to jam the helicase activity of eIF4A in a fraction of assembled 48S complexes...
February 5, 2018: Nucleic Acids Research
Guillermo R Lázaro, Suchetana Mukhopadhyay, Michael F Hagan
During the lifecycle of many enveloped viruses, a nucleocapsid core buds through the cell membrane to acquire an outer envelope of lipid membrane and viral glycoproteins. However, the presence of a nucleocapsid core is not required for assembly of infectious particles. To determine the role of the nucleocapsid core, we develop a coarse-grained computational model with which we investigate budding dynamics as a function of glycoprotein and nucleocapsid interactions, as well as budding in the absence of a nucleocapsid...
February 6, 2018: Biophysical Journal
Heidi Auerswald, Camille Boussioux, Saraden In, Sokthearom Mao, Sivuth Ong, Rekol Huy, Rithea Leang, Malen Chan, Veasna Duong, Sowath Ly, Arnaud Tarantola, Philippe Dussart
Chikungunya virus (CHIKV) is an alphavirus circulating worldwide. Its presence in Asia has been reported since the 1950s, constituting the Asian genotype. Since 2005, strains from the Eastern, Central, and Southern African (ECSA) genotype have caused several outbreaks across Asia. Viruses from the ECSA genotype were also detected in Cambodia in late 2011 and led to an outbreak in a rural community in 2012. A former investigation from 2012 found a higher risk of infection in people younger than 40 years, suggesting a pre-existing herd immunity in the older Cambodian population due to infection with an Asian genotype...
February 7, 2018: Emerging Microbes & Infections
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