: Following its discovery in California in 1962, enterovirus D68 (EV-D68) was reported only sporadically around the world. In August 2014, a marked increase of EV-D68 cases in young children with severe respiratory infections was reported in the USA and Canada and later in Europe and Asia. Some of these cases were also found to be associated with acute flaccid paralysis, which exacerbated public health concern, and has since triggered international efforts to strengthen both EV-D68 and acute flaccid paralysis surveillance systems. This review summarizes the current knowledge on EV-D68, offering an overview of EV-D68 epidemiology, clinical presentations, diagnostic methodologies, and treatment strategies, as well as surveillance and outbreak management.
Mayaro fever is an emerging acute viral disease endemic in Central and South America. Mayaro virus (MAYV) is classified in the Semliki Forest virus antigenic complex and shares similarities with the alphavirus Chikungunya virus and the flavivirus Dengue virus. MAYV is an arbovirus transmitted by Haemagogus janthinomys , with competence also demonstrated in Aedes aegypti, Aedes scapularis , and Anopheles quadrimaculatus . Outbreaks and small epidemics of Mayaro fever have occurred in several countries in northern South America and the Caribbean. In addition, travel-associated cases have been reported in European nationals returning from endemic areas. Clinical features of Mayaro fever include fever, chills, persistent arthralgia, retro-orbital pain, maculopapular rash, itching, dizziness, and, rarely, lymphadenopathy. Methods of control for MAYV are similar to those used for other sylvatic arboviruses. Although MAYV was discovered as long ago as the 1950s and continues to be prevalent in the tropical areas of the Americas, it remains neglected and under-studied. This paper provides a thorough and current review of the published MAYV literature ranging from its original description to modern outbreaks, and from the basic virus characteristics to the clinical and epidemiological aspects of this disease. Keywords: Mayaro virus, emerging arbovirus, dengue-like virus, arthrogenic virus
Lujo virus (LUJV), a novel Old World arenavirus, was found to cause a fulminant viral hemorrhagic fever syndrome in an outbreak in 2008. The primary patient was from Lusaka, Zambia, and subsequent nosocomial transmission occurred to four other patients in Johannesburg, South Africa, hence the name Lujo virus. Like all arenaviruses, LUJV is a segmented, single-stranded, negative-sense RNA virus. Genomic sequencing confirmed that LUJV G1 glycoprotein was novel, diverse and genetically equidistant from other arenaviruses. A clinical syndrome resembling severe, fulminant Lassa virus infection was responsible for a high case fatality rate of 80% (4/5 cases). This review describes briefly the clinical course of the disease, laboratory findings and diagnosis. Recent studies address the current aspects of epidemiology, pathophysiology and treatments, specifically comparing with Lassa virus. Keywords: Lujo virus, viral hemorrhagic fever, outbreak, epidemiology, pathophysiology, treatment
Scientific attention has focused recently on the link between Guillain–Barrè syndrome (GBS) and Zika virus (ZIKV). Two related questions emerged: 1) what triggered the violent 2014 outbreak of a virus, which, first identified in 1947, had caused only a limited number of documented cases of human infection until 2007 and 2) which molecular mechanism(s) relate ZIKV active infection to GBS, an autoimmune inflammatory polyradiculoneuropathy. Capitalizing on the increased interest on ZIKV and hypothesizing the involvement of autoimmune mechanisms, we searched for minimal epitopic determinants shared between ZIKV and other GBS-related pathogens – namely, Epstein–Barr virus, human cytomegalovirus, influenza virus, Campylobacter jejuni , and Mycoplasma pneumoniae , among others – and human proteins that, when altered, have been associated with myelin disorders and axonopathies. We report a considerable peptide matching that links GBS-related pathogens to human proteins related to myelin disorders and axonopathies. Crucially, the shared pentapeptides repeatedly occur throughout numerous epitopes validated as immunopositive by a conspicuous scientific literature. The data support a scenario where multiple different infections over time and resulting multiple cross-reactions may contribute to the pathogenesis of GBS. In practice, previous infection(s) might create immunologic memory able to trigger uncontrolled hyperimmunogenicity during a successive pathogen exposure. ZIKV pandemic appears to be an exemplar model for a proof-of-concept of such multiple cross-reactivity mechanism. Keywords: peptide sharing, GBS-related human proteins, GBS-related pathogens, multiple cross reactivity, hyperimmunogenicity
: The Flavivirus genus (Flaviviridae family) contains important pathogens such as yellow fever virus, Japanese encephalitis virus, St Louis encephalitis virus, West Nile virus, Usutu virus (USUV), Zika virus, and dengue virus, many of which constitute a worrisome threat to global human and animal health. USUV is transmitted by mosquitoes and, as any other flavivirus, is an enveloped plus-strand RNA virus. The virus was first isolated from Culex neavei mosquitoes in South Africa in 1959 near the Usutu River, from where it takes its name. Since then, the virus was confined to Africa until its first detection in Austria in 2001, although it was probably present in Europe since 1996 or even earlier. After that, USUV has spread throughout Europe, causing a considerable mortality among birds and a few neurologic cases in humans. The main USUV natural hosts are birds, but infection has also been reported in other vertebrate species, including humans. The fast spread of the virus through the continent, the relatively high mortality caused in birds, and the recent neuroinvasive human cases related to USUV infection reported in Europe have raised serious concerns about its possible consequences for public health. Here, an updated review of current knowledge about this emerging pathogen is presented.
Fil: Juliarena, Marcela Alicia. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Conicet - Tandil. Centro de Investigacion Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigacion Veterinaria de Tandil. Provincia de Buenos Aires. Gobernacion. Comision de Investigaciones Cientificas. Centro de Investigacion Veterinaria de Tandil; Argentina
Coat proteins (CPs) are the most abundant protein produced during a viral infection. CPs have been shown to regulate the infection processes of RNA viruses, including RNA replication and gene expression. The numerous activities of the CP in infection are likely to require regulation, possibly through posttranslational modifications. Protein posttranslational modifications are involved in signal transduction, expanding and regulating protein function, and responding to changes in the environment. Accumulating evidence suggests that phosphorylation of viral CPs is involved in the regulation of the viral infection process from enabling virion disassembly to regulation of viral protein synthesis and replication. CP phosphorylation also affects viral trafficking and virion assembly. This review focuses on the regulatory roles that phosphorylation of CPs has in the life cycle of viruses with RNA genomes. Keywords: viral capsid protein, posttranslational modification, phosphorylation, protein–RNA interaction
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Viral infections and pandemics result in millions of deaths worldwide each year. Viruses exploit host cellular processes, not only to gain entry and to deliver their genetic cargo, but also to counteract and use host immune defenses. To this end, a variety of ingenious strategies have evolved in viruses that involve fusion between virus and host membranes, channel formation through the host plasma membranes, disruption of the membrane vesicles, or a combination of these events. The entry and infection pathways of virus are thus largely defined by the interactions between virus particles and their cell surface and cytoplasmic receptors. A thorough analysis of virus–host interactomes may reveal novel mechanisms in virus entry, virus infection, and pathogenic strategies to modulate host metabolic pathways. The study of viral entry, infection, and pathogenesis has evolved over a long period. A host of next-generation technological advancements in this field has been discussed in this review. Keywords: RNA interference, high-throughput, bioinformatics, viral entry, viral infection, virus–host interactions
Foot-and-mouth disease remains one of the world's most economically important diseases of livestock. It is caused by foot-and-mouth disease virus, a member of the picornavirus family. The virus replicates very rapidly and can be efficiently transmitted between hosts by a variety of routes. The disease has been effectively controlled in some parts of the world but remains endemic in many others, thus there is a constant risk of introduction of the disease into areas that are normally free of foot-and-mouth disease with potentially huge economic consequences. To reduce the need for large-scale culling of infected, and potentially infected, animals there has been significant effort to develop new vaccines against this disease which avoid some, or all, of the deficiencies of current vaccines. A major focus has been on the use of systems that express the structural proteins of the virus that self-assemble to generate “empty capsid” particles which share many features with the intact virus but lack the ribonucleic acid genome and are therefore non-infectious. Such particles can be “designed” to improve their stability or modify their antigenicity and can be produced without “high containment” facilities. The development and use of such improved vaccines should assist in the global efforts to control this important disease. Keywords: picornavirus, diagnostic assays, virus structure, infection, immune responses
Enteric viruses are major contributors to foodborne disease, and include adenovirus, astrovirus, rotavirus, sapovirus, hepatitis A and E viruses, and norovirus. From a foodborne transmission perspective, norovirus is the most important; however, hepatitis A is associated with more serious illness. Foodborne viruses are transmitted through contaminated food, but also in combination with person-to-person contact or through environmental contamination. These viruses survive well in the environment, are excreted in abundance in feces, and have a low infectious dose, all of which facilitate spread within a community. Many colonized individuals experience mild gastroenteritis lasting a few days or are asymptomatic, although viral excretion may continue over days or weeks. Severe illness tends to be restricted to the very young and elderly, especially in closed communities such as schools and homes for the aged. In the USA, norovirus is considered to be responsible for two thirds of all foodborne illnesses occurring in a wide range of institutional settings, including schools, colleges, child care centers, cruise ships, prisons, and soldiers on campaign. Norovirus outbreaks also occur at one-time events, such as banquets, wedding receptions, birthday parties, and potluck meals, and are most often introduced by infected food workers producing, preparing, or serving food, or through self-service buffets. Often the infections are introduced from the community into institutions where they can infect the majority of residents unless quickly controlled. In countries where economic assessments have been completed, there is a high cost for prevention, control, and treatment of infections. Control measures are limited, but include proper clean-up and disinfection after vomiting or diarrhea, and prevention of food contact by infected individuals. As diagnostics improve, more foodborne illnesses relating to enteric viruses are expected to be identified, especially in developing countries where there are little data today. Keywords: foodborne, enteric viruses, shellfish, food workers, prevention, control, ready-to-eat food
Cobicistat (Cobi) is a pharmacoenhancer, without anti-HIV activity, that optimizes systemic exposures of protease inhibitors (PIs) such as atazanavir (ATV) and darunavir (DRV). In particular, Cobi is a potent inhibitor of cytochrome P450 (CYP) 3A enzymes, the main metabolizing pathway of this class of antiretrovirals. Due to its more selective inhibition of CYP3A, Cobi has a lower potential for off-target drug interactions than the standard boosting agent ritonavir (RTV), and lower likelihood for enzymatic induction. In pharmacokinetic studies of healthy volunteers, DRV boosted with Cobi attains plasma concentrations that are comparable to those achieved with 100 mg RTV as booster. In Phase III clinical trials, conducted in naïve subjects, the coformulation yielded high rates of suppression of viral replication, on average 82%–83% of treated patients reaching undetectable viremia after 48 weeks of therapy. The selection of resistance associated with mutations was a rare event and no phenotypic resistance to DRV emerged in viral failures. Generally, Cobi was well tolerated; however, it has been shown to decrease estimated creatinine clearance (ClCr) due to inhibition of tubular secretion of creatinine. Cobi, therefore, should not be initiated in patients with ClCr less than 70 mL/min, if any coadministered agent (eg, emtricitabine, lamivudine, tenofovir disoproxil fumarate, or adefovir) requires dose adjustment based on ClCr.DRV/Cobi fixed-dose combination is part of an important evolution of antiretroviral therapy toward simpler yet potent formulations. In this setting, it is important to combine potency, simplicity, safety, and high genetic barrier, as in this case. Keywords: HIV, darunavir, Cobicistat, fixed dose, pharmacoenhancer
Oncolytic viruses are a promising experimental anticancer therapy currently undergoing clinical translation. The development of oncolytic virotherapy offers a potential solution to the elusive “one-shot”cancer cure by providing targeted therapy to selectively infect and kill cancer cells while provoking adaptive anticancer immune responses as protection against distant metastasis and recurrent tumor challenge. While this technology has overcome barriers to safety and efficacy through cancer-specific targeting techniques, in order to reach full therapeutic potential, oncolytic therapies must still overcome barriers to intratumoral delivery and spread that result in heterogeneous intratumoral delivery and nonuniform response. This review will discuss barriers to oncolytic virotherapy translation related to mechanisms of delivering virus via tumor vasculature and distributing virus throughout the tumor microenvironment. Barriers include extravasation into the tumor that is dependent on adequate blood flow, tissue perfusion, and tumoral enhanced permeability and retention for transvascular transport. Subsequently, virions must undergo interstitial transport against dense stromal barriers and high interstitial fluid pressure to initiate infection. In order to achieve massive tumor regression, infection must spread to cover large volumes of tumor mass. Furthermore, virus bioavailability is quickly dampened upon systemic administration due to neutralization and sequestration. These barriers to delivery limit the amount of virus that effectively reaches and spreads within the tumor, forcing dose increases that impinge upon limits of production and increase possibility of adverse events. Techniques to overcome these barriers are discussed but largely remain to be translated into clinical use. Keywords: oncolytic virotherapy, barriers, delivery, systemic therapy, translation
License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Limited. Information on how to request permission may be found at: http://www.dovepress.com/permissions.php Virus Adaptation and Treatment 2015:7 1–9 Virus Adaptation and Treatment Dovepress
License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Limited. Information on how to request permission may be found at: http://www.dovepress.com/permissions.php Virus Adaptation and Treatment 2014:6 33–36 Virus Adaptation and Treatment Dovepress
Keywords: latent viruses, autoimmune conditions, biological therapies, reactivation
Correspondence: Kelli L Barr 2055 Mowry Road, Box 100009, Gainesville, FL, USA Tel +1 352 294 5317 Fax +1 352 273 9420 Email ateraxes@hotmail.com Background: Globally, dengue viruses (DENV) are the most common human arboviral infection and the most important public health threat from mosquito-borne viral pathogens. Recent work has indicated that DENV affinity for cell lines is serotype-specific, which raises challenging questions regarding DENV-host interactions as well as the development of therapeutics and control programs. Methods: We evaluated the infectious capacity of 11 strains of DENV for serotypes 1–4 in 17 distinct cell lines. The cell lines were evaluated for virus susceptibility via immunohistochemistry and quantitative reverse transcription polymerase chain reaction. Results: Both methods demonstrated the ability of DENV to replicate in all cell lines, with viral titers ranging from 1 × 10 to 1 × 10 infectious units per mL. Cell line susceptibility to DENV infection was strain-specific, with DENV-4 strains infecting more cell lines than the other serotypes. DENV-2 New Guinea C and DENV-4 H241 were detected in more cell lines than any other strains. Viral fusion assays indicated that DENV requirements for fusion are strain-specific. Conclusion: These data indicate that several cell lines can be used to culture and study DENV. The strain-specific susceptibility for certain cell lines may provide a tool for characterizing specific DENV strains and an in vitro platform for the development and optimization of therapeutics, the study of host-pathogen interactions, and ecological studies on the cocirculation of DENV strains in a specific region or individual.
Since its first isolation in Germany in 2011 the Schmallenberg strain of the Sathuperi virus has been detected across northern Europe. The virus is associated with neurological disease, abortion, and congenital deformities in ruminants, particularly among sheep and cattle. The rapid dissemination of the pathogen is reminiscent of the transmission of another midge-borne arbovirus, Bluetongue virus , which also spread to Europe on several separate occasions between 1998 and 2007. In this review we detail the characteristic features of the Schmallenberg virus and consider whether the virus highlights a European vulnerability for other midge-transmitted pathogens. Keywords: Schmallenberg, Sathuperi, Culicoides, bunyavirus, midge, bluetongue
Epstein–Barr virus is a member of the human herpes virus family. Primary infection is usually asymptomatic in childhood; in adolescents and young adults, however, it leads to infectious mononucleosis with symptoms including fever, fatigue, and sore throat that can persist for months. The disease is usually self-limited and resolves over a period of weeks or months but may occasionally be complicated by a wide variety of complications. Symptomatic treatment, the cornerstone of therapy, includes adequate hydration, analgesics, antipyretics, and limitations of contact sports and activities. The role of antiviral treatment and corticosteroids is debatable and not recommended in general, while the development of vaccination is under investigation. This review concentrates on the diagnosis, the potential complications, and the therapeutic strategies in patients with infectious mononucleosis. Keywords: Epstein–Barr virus, infectious mononucleosis, EBV
Atripla is the first once-daily, single-tablet, triple-combination antiretroviral therapy. It is recommended for the initial treatment of the naïve patient with human immunodeficiency virus-1 (HIV-1) infection in all current guidelines, based on its proven efficacy in numerous head-to-head randomized clinical trials. Not only has it proven efficacy, but the fixed-dose combination, Atripla, has resulted in an improvement in adherence, quality of life, and satisfaction among naïve as well as virally suppressed patients switching from another regimen. Despite the advantages, tolerability issues can arise that are related primarily to the efavirenz component, which is known to cause central nervous side effects such as dizziness, abnormal dreams, and anxiety. Although generally self-limited, these side-effects can lead to treatment discontinuation in the short- or long-term. Based on the observation of neural tube defects in macaque models, and isolated case reports in human fetuses with first trimester exposure, it is rated as Food and Drug Administration pregnancy category D, and considered as contraindicated in the first trimester of pregnancy where alternatives are available. Given the low genetic barrier of each of the individual components, resistance remains an important issue for patients with poor adherence, but is balanced in part by the long half-life of the drugs. Transmitted resistance is described in up to 16% of newly infected patients in population surveys, and is particularly prevalent in men who have sex with men. Minority variants that may impart resistant to efavirenz are not detected with currently used HIV-1 genotype assays, but nonetheless may also be implicated in patients who fail initial treatment. Several single-tablet regimens are recently licensed or in development that will challenge Atripla as the single-tablet first-line option, but none have shown superior efficacy to date. Keywords: Atripla, adherence, HIV, resistance, fixed-dose, efavirenz
