Showing papers in "Reviews in Medical Virology in 2012"

Chromosomally integrated human herpesvirus 6: questions and answers

Abstract: Chromosomally integrated human herpesvirus 6 (ciHHV-6) is a condition in which the complete HHV-6 genome is integrated into the host germ line genome and is vertically transmitted in a Mendelian manner. The condition is found in less than 1% of controls in the USA and UK, but has been found at a somewhat higher prevalence in transplant recipients and other patient populations in several small studies. HHV-6 levels in whole blood that exceed 5.5 log10 copies/ml are strongly suggestive of ciHHV-6. Monitoring DNA load in plasma and serum is unreliable, both for identifying and for monitoring subjects with ciHHV-6 due to cell lysis and release of cellular DNA. High HHV-6 DNA loads associated with ciHHV-6 can lead to erroneous diagnosis of active infection. Transplant recipients with ciHHV-6 may be at increased risk for bacterial infection and graft rejection. ciHHV-6 can be induced to a state of active viral replication in vitro. It is not known whether ciHHV-6 individuals are put at clinical risk by the use of drugs that have been associated with HHV-6 reactivation in vivo or in vitro. Nonetheless, we urge careful observation when use of such drugs is indicated in individuals known to have ciHHV-6. Little is known about whether individuals with ciHHV-6 develop immune tolerance for viral proteins. Further research is needed to determine the role of ciHHV-6 in disease. Copyright © 2011 John Wiley & Sons, Ltd.

Human bocavirus—the first 5 years

Abstract: SUMMARY Four species of human bocavirus (HBoV) have been recently discovered and classified in the Bocavirus genus (family Parvoviridae, subfamily Parvovirinae). Although detected both in respiratory and stool samples worldwide, HBoV1 is predominantly a respiratory pathogen, whereas HBoV2, HBoV3, and HBoV4 have been found mainly in stool. A variety of signs and symptoms have been described in patients with HBoV infection including rhinitis, pharyngitis, cough, dyspnea, wheezing, pneumonia, acute otitis media, fever, nausea, vomiting, and diarrhea. Many of these potential manifestations have not been systematically explored, and they have been questioned because of high HBoV co-infection rates in symptomatic subjects and high HBoV detection rates in asymptomatic subjects. However, evidence is mounting to show that HBoV1 is an important cause of lower respiratory tract illness. The best currently available diagnostic approaches are quantitative PCR and serology. This concise review summarizes the current clinical knowledge on HBoV species. Copyright © 2011 John Wiley & Sons, Ltd.

Japanese encephalitis and Japanese encephalitis virus in mainland China.

Abstract: Japanese encephalitis (JE), caused by Japanese encephalitis virus (JEV) infection, is the most important viral encephalitis in the world. Approximately 35,000-50,000 people suffer from JE every year, with a mortality rate of 10,000-15,000 people per year. Although the safety and efficacy of JE vaccines (inactivated and attenuated) have been demonstrated, China still accounts for 50% of the reported JE cases worldwide. In this review, we provide information about the burden of JE in mainland China and the corresponding epidemiology from 1949 to 2010, including the morbidity and mortality of JE; the age, gender, and vocational distribution of JE cases; its regional and seasonal distribution; and JE immunization. In addition, we discuss the relationships among vectors, hosts, and JEV isolates from mainland China; the dominant vector species for JEV transmission; the variety of JEV genotypes and the different biological characteristics of the different JEV genotypes; and the molecular evolution of JEV.

Neuroinvasive flavivirus infections

Abstract: Flaviviruses, including Dengue, West Nile, Japanese encephalitis, and Tick-borne encephalitis virus, are major emerging human pathogens, affecting millions of individuals worldwide. Many clinically important flaviviruses elicit CNS diseases in infected hosts, including traditional "hemorrhagic" viruses, such as Dengue. This review focuses on the epidemiology, symptomatology, neuropathology, and, specifically, neuropathogenesis of flavivirus-induced human CNS disease. A detailed insight into specific factors priming towards neuroinvasive disease is of clear clinical significance, as well as importance to the development of antiviral therapies and identification of key mechanisms involved in the (re)emergence of specific flaviviruses, including potentially novel or previously unrecognized ones, as neuroinvasive pathogens.

Contribution of antibody production against neuraminidase to the protection afforded by influenza vaccines

Abstract: Vaccines are instrumental in controlling the burden of influenza virus infection in humans and animals. Antibodies raised against both major viral surface glycoproteins, hemagglutinin (HA) and neuraminidase (NA), can contribute to protective immunity. Vaccine-induced HA antibodies have been characterized extensively, and they generally confer protection by blocking the attachment and fusion of a homologous virus onto host cells. Although not as well characterized, some functions of NA antibodies in influenza vaccine-mediated immunity have been recognized for many years. In this review, we summarize the case for NA antibodies in influenza vaccine-mediated immunity. In the absence of well-matched HA antibodies, NA antibodies can provide varying degrees of protection against disease. NA proteins of seasonal influenza vaccines have been shown in some instances to elicit serum antibodies with cross-reactivity to avian-origin and swine-origin influenza strains, in addition to HA drift variants. NA-mediated immunity has been linked to (i) conserved NA epitopes amongst otherwise antigenically distinct strains, partly attributable to the segmented influenza viral genome; (ii) inhibition of NA enzymatic activity; and (iii) the NA content in vaccine formulations. There is a potential to enhance the effectiveness of existing and future influenza vaccines by focusing greater attention on the antigenic characteristics and potency of the NA protein.

Neutralizing human monoclonal antibodies to severe acute respiratory syndrome coronavirus: target, mechanism of action, and therapeutic potential

Abstract: The emergence of Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) led to a rapid response not only to contain the outbreak but also to identify possible therapeutic interventions, including the generation of human monoclonal antibodies (hmAbs). hmAbs may be used therapeutically without the drawbacks of chimeric or animal Abs. Several different methods have been used to generate SARS-CoV specific neutralizing hmAbs including the immunization of transgenic mice, cloning of small chain variable regions from naive and convalescent patients, and the immortalization of convalescent B cells. Irrespective of the techniques used, the majority of hmAbs specifically reacted with the receptor binding domain (RBD) of the spike (S) protein and likely prevented receptor binding. However, several hmAbs that can bind to epitopes either within the RBD, located N terminal of the RBD or in the S2 domain, and neutralize the virus with or without inhibiting receptor binding have been identified. Therapeutic utility of hmAbs has been further elucidated through the identification of potential combinations of hmAbs that could neutralize viral variants including escape mutants selected using hmAbs. These results suggest that a cocktail of hmAbs that can bind to unique epitopes and have different mechanisms of action might be of clinical utility against SARS-CoV infection, and indicate that a similar approach may be applied to treat other viral infections.

Hepatitis C virus entry: beyond receptors

Abstract: HCV is a blood-borne pathogen that affects approximately 3% of the global population and leads to progressive liver disease Recent advances have identified an essential role for host cell molecules: tetraspanin CD81, scavenger receptor B1 and the tight junction proteins claudin-1 and occludin in HCV entry, suggesting a complex multi-step process The conserved nature of this receptor-dependent step in the viral life cycle offers an attractive target for therapeutic intervention Evidence is emerging that additional factors other than classical receptors, such as inflammatory mediators regulate the ability of hepatocytes to support HCV entry, and as such may provide potential avenues for drug design and development In this review, we summarise the recent literature on HCV entry mechanisms with a view to realising the future potential of therapeutically targeting this process

Phosphorylation events during viral infections provide potential therapeutic targets.

Abstract: For many medically relevant viruses, there is now considerable evidence that both viral and cellular kinases play important roles in viral infection. Ultimately, these kinases, and the cellular signaling pathways that they exploit, may serve as therapeutic targets for treating patients. Currently, small molecule inhibitors of kinases are under investigation as therapy for herpes viral infections. Additionally, a number of cellular or host-directed tyrosine kinase inhibitors that have been previously FDA approved for cancer treatment are under study in animal models and clinical trials, as they have shown promise for the treatment of various viral infections as well. This review will highlight the wide range of viral proteins phosphorylated by viral and cellular kinases, and the potential for variability of kinase recognition sites within viral substrates to impact phosphorylation and kinase prediction. Research studying kinase-targeting prophylactic and therapeutic treatments for a number of viral infections will also be discussed.

Beneficial actions of melatonin in the management of viral infections: a new use for this "molecular handyman"?

Abstract: Melatonin (N-acetyl-5-methoxytryptamine) is a multifunctional signaling molecule that has a variety of important functions. Numerous clinical trials have examined the therapeutic usefulness of melatonin in different fields of medicine. Clinical trials have shown that melatonin is efficient in preventing cell damage under acute (sepsis, asphyxia in newborns) and chronic states (metabolic and neurodegenerative diseases, cancer, inflammation, aging). The beneficial effects of melatonin can be explained by its properties as a potent antioxidant and antioxidant enzyme inducer, a regulator of apoptosis and a stimulator of immune functions. These effects support the use of melatonin in viral infections, which are often associated with inflammatory injury and increases in oxidative stress. In fact, melatonin has been used recently to treat several viral infections, which are summarized in this review. The role of melatonin in infections is also discussed herein.

Progressive multifocal leukoencephalopathy: Clinical and molecular aspects

Abstract: The fatal CNS demyelinating disease, progressive multifocal leukoencephalopathy (PML), is rare and appears to occur almost always as a consequence of immune dysfunction. Thus it is associated with HIV/AIDS and also as a side-effect of certain immunomodulatory monoclonal antibody therapies. In contrast to the rarity of PML, the etiological agent of the disease, the polyomavirus JC (JCV) is widespread in populations worldwide. In the forty years since JCV was first isolated, much has been learned about the virus and the disease from laboratory and clinical observations. However, there are many aspects of the viral life cycle and the pathogenesis of the disease that still remain unclear and our understanding is constantly evolving. In this review, we will discuss our current understanding of the clinical features of PML and molecular characteristics of JCV and how they relate to each other. Clinical observations can inform molecular studies of the virus and likewise molecular findings concerning the life cycle of the virus can guide the development of novel therapeutic strategies.

Genome analysis of the new human polyomaviruses

Abstract: SUMMARY Polyomaviridae is a growing family of naked, double-stranded DNA viruses that infect birds and mammals. The last few years, several new members infecting birds or primates have been discovered, including seven human polyomaviruses: KI, WU, Merkel cell polyomavirus, HPyV6, HPyV7, trichodysplasia spinulosa-associated polyomavirus, and HPyV9. In addition, DNA and antibodies against the monkey lymphotropic polyomavirus have been detected in humans, indicating that this virus can also infect man. However, little is known about the route of infection, transmission, cell tropism, and, with the exception of Merkel cell polyomavirus and trichodysplasia spinulosa-associated polyomavirus, the pathogenicity of these viruses. This review compares the genomes of these emerging human polyomaviruses with previously known polyomaviruses detected in man, reports mutations in different isolates, and predicts structural and functional properties of their viral proteins. Copyright © 2012 John Wiley & Sons, Ltd.

Hepatitis E virus: neutralizing sites, diagnosis, and protective immunity.

Abstract: There have been increased attentions on HEV and its associated diseases in recent years as a result of an increased number of reports on autochthonous patients from many developed countries. Vaccine development and better disease management are expected from protective immunity with increased knowledge on the pathogenesis and virology of HEV. This review summarizes the current understanding of the HEV virology, the key neutralization sites (epitopes) on the surface of the viral capsid, the host humoral immune responses for HEV infection, and the protective immunity conferred by natural infection and vaccination. Recombinant VLPs were prepared to mimic the protective and neutralizing epitopes on the virion surface, thus being capable of eliciting protective immunity when injected to nonhuman primates or human volunteers during preclinical tests and clinical trials. Four markers-viral RNA, anti-HEV IgM, anti-HEV IgG, and low avidity of anti-HEV IgG-are important in the diagnosis of HEV infection, particularly for patients presenting with acute hepatitis symptoms. This toolbox of genomic and immunological assays is valuable in furthering our understanding of the time course of HEV infection and the subsequent hepatitis during preclinical and clinical development of an efficacious vaccine. Two vaccine candidates had shown good tolerability, high immunogenicity, and high efficacy against symptomatic and/or asymptomatic HEV infection. One of them has been licensed in China recently. However, many issues need to be resolved before new technological progresses can benefit the people who need them most.

Picobirnavirus infections: viral persistence and zoonotic potential

Abstract: Picobirnaviruses (PBVs) are small, non-enveloped, bisegmented double-stranded RNA genomic viruses of vertebrate hosts. Since their discovery in the late 1980s in clinical specimens from outbreaks of acute gastroenteritis in children, significant efforts have been made to investigate the role of PBV in diarrheic diseases. PBV has been detected in sporadic episodes of diarrhea as sole pathogen or coinfection as well as in outbreaks of acute gastroenteritis and in immunocompromised patients with diarrhea. However, PBV is frequently detected in non-diarrheic healthy hosts, and prolonged shedding has been observed in some individuals. Of interest, similar patterns of PBV infection have also been observed in pigs and other animal hosts. The increasing amount of PBV sequence data gathered from molecular epidemiological studies has evidenced a great sequence diversity of PBVs in various hosts and environmental samples. Importantly, evidence has been found for genetic relatedness between human and animal PBV strains, suggesting extant crossing points in the ecology and evolution of heterologous PBV strains. At present, no cell culture and animal model exists for PBVs. Well-structured epidemiological studies are still the only alternative to demonstrate the potential etiological role of PBVs in acute gastroenteritis or other diseases. This review aims to analyze the public health aspects of PBV infection, especially its possible association with zoonosis.

HIV-1 infection and neurocognitive impairment in the current era

Abstract: Brain HIV-1-infection may result in a syndrome of profound cognitive, behavioral and motor impairment known as AIDS dementia complex (ADC) in adults and HIV-related encephalopathy in children. Although the introduction of highly active antiretroviral therapy (HAART) has prolonged and improved the lives of infected individuals, it is clear that HAART does not provide complete protection against neurological damage in HIV/AIDS. HIV-1 associated dementia is a complex phenomenon, which could be the result of several mechanisms caused by those players using different intracellular signaling pathways. Understanding the causes of neurodegeneration during HIV-1 infection and the factors which certain individuals develop disease can provide researches on new therapeutic targets to positively affect disease outcomes. Controlling CNS viral replication with HAART is an essential primary approach, but it should be complemented with adjunctive CNS-directed therapeutics. Understanding the nature of HIV-1 infection within the CNS as well as inflammatory responses will ultimately lead to the elimination of HIV-associated neurocognitive disorders.

Respiratory syncytial virus infection and immunity

Abstract: Respiratory syncytial virus (RSV) is the leading cause for childhood hospitalization and respiratory distress, being recognized as a major health and economic burden worldwide. RSV can exploit host immunity and cause a strong inflammatory response that leads to lung damage and virus dissemination. Unfortunately, the immune response elicited by RSV normally fails to protect against subsequent exposures to the virus. Despite intense research during the 50 years after the discovery of RSV, scientists are just beginning to understand the mechanisms contributing to pathology and to the inadequate immune response shown by susceptible individuals. Here, we discuss some of the most important advances made in this field that could lead to the development of new prophylactic tools.

Making the case: married versus separate models of alphaherpes virus anterograde transport in axons.

Abstract: Alphaherpesvirus virions infect neurons and are transported in axons for long distance spread within the host nervous system. The assembly state of newly made herpesvirus particles during anterograde transport in axons is an essential question in alphaherpesvirus biology. The structure of the particle has remained both elusive and controversial for the past two decades, with conflicting evidence from EM, immunofluorescence, and live cell imaging studies. Two opposing models have been proposed-the Married and Separate Models. Under the Married Model, infectious virions are assembled in the neuronal cell body before sorting into axons and then traffic inside a transport vesicle. Conversely, the Separate Model postulates that vesicles containing viral membrane proteins are sorted into axons independent of capsids, with final assembly of mature virions occurring at a distant egress site. Recently, a complementary series of studies employing high-resolution EM and live cell fluorescence microscopy have provided evidence consistent with the Married Model, whereas other studies offer evidence supporting the Separate Model. In this review, we compare and discuss the published data and attempt to reconcile divergent findings and interpretations as they relate to these models.

Hepatitis C core Ag and its clinical applicability: potential advantages and disadvantages for diagnosis and follow-up?

Abstract: SUMMARY Chronic hepatitis C virus (HCV) infection which is often a silent disease has resulted in a global epidemic. The diagnosis of hepatitis C virus often requires confirmation with molecular techniques such as the polymerase chain reaction for detection of HCV RNA. Following laboratory confirmation of the diagnosis, molecular techniques are routinely used to monitor HCV RNA levels, particularly in those undergoing treatment. Unfortunately, molecular tests are relatively expensive and their cost may be prohibitive in the developing world. Several studies have investigated the applicability of the hepatitis C core Ag (HCVcAg), as a substitute for measuring HCV RNA levels. In this review, we provide an overview of the major findings of these studies focused on the utility of measuring HCVcAg antigen levels in the clinical setting. Overall, measuring HCVcAg levels is associated with several advantages and disadvantages. It may be useful in different clinical settings for monitoring HCV patients after obtaining an initial baseline HCV RNA result. Copyright © 2011 John Wiley & Sons, Ltd.

Innate immune interferon responses to human immunodeficiency virus-1 infection.

Abstract: Type I interferon (IFN) responses represent the canonical host innate immune response to viruses, which serves to upregulate expression of antiviral restriction factors and augment adaptive immune defences. There is clear evidence for type I IFN activity in both acute and chronic HIV-1 infection in vivo, and plasmacytoid dendritic cells have been identified as one important source for these responses, through innate immune detection of viral RNA by Toll-like receptor 7. In addition, new insights into the molecular mechanisms that trigger induction of type I IFNs suggest innate immune receptors for viral DNA may also mediate these responses. It is widely recognised that HIV-1 restriction factors share the characteristic of IFN-inducible expression, and that the virus has evolved to counteract these antiviral mechanisms. However, in some target cells, such as macrophages, IFN can still effectively restrict virus. In this context, HIV-1 shows the ability to evade innate immune recognition and thereby avoid induction of type I IFN in order to successfully establish productive infection. The relative importance of evasion of innate immune detection and evasion of IFN-inducible restriction in the natural history of HIV-1 infection is not known, and the data suggest that type I IFN responses may play a role in both viral control and in the immunopathogenesis of progressive disease. Further study of the relationship between HIV-1 infection and type I IFN responses is required to unravel these issues and inform the development of novel therapeutics or vaccine strategies.

Next-generation treatment strategies for human papillomavirus-related head and neck squamous cell carcinoma: where do we go?

Abstract: Oncogenic human papillomavirus (HPV) is currently recognised as a major risk factor for the development of head and neck squamous cell carcinomas (HNSCC). HPV is mostly detected in tumours arising from the oropharynx and more specifically from the tonsil. HPV-related tumours display clinical and molecular characteristics that are distinct from HPV-unrelated tumours, which are generally induced by alcohol and tobacco abuse. Detection of biologically active HPV in HNSCC has prognostic relevance, which warrants the separate classification of HPV-induced tumours and is a prerequisite for further optimisation of treatment protocols for this distinct group. Current guidelines for the treatment of oropharyngeal squamous cell carcinoma (OPSCC) have not incorporated specific treatment modalities for HPV-related tumours. The development of such treatment options is still in a preclinical phase or in early clinical trials. Recent data on treatment response of OPSCC have been obtained by retrospectively analysing HPV-status and indicate that patients with HPV-related tumours show a favourable prognosis, independent of the type of treatment. These patients may benefit from de-intensified treatment, which should be assessed in prospective clinical trials. The development and future use of new antiviral and immunomodulatory therapeutics may be instrumental in this approach to improve survival rates and decrease disease-and-treatment-related morbidity. In this review we will focus on present therapeutic HPV-targeting strategies and discuss future directions for de-intensified treatment of HPV-positive HNSCC.

Sensing herpes: more than toll

Abstract: To launch an effective antiviral immune response, cells must recognize the virus, activate a cytokine response, and initiate inflammatory processes. Herpes simplex virus 1 (HSV-1) and HSV-2 are nuclear-replicating viruses composed of a double-stranded DNA genome plus glycoproteins that are incorporated into a lipid bilayer envelope that surrounds an icosahedral capsid. Several novel receptors that mediate innate recognition of HSV and that activate the innate immune response have been identified in recent years. The host-virus interactions that lead to type I interferon (IFN), type III IFN, and cytokine production include cellular recognition of viral envelope and structural proteins, recognition of viral genomic DNA and recognition of virus-derived double-stranded RNAs. Such RNAs can interact with cellular pattern-recognition receptors, including Toll-like receptors and a number of cytoplasmic and nuclear receptors for virus DNA and virus-derived RNAs. In this review, I present a systematic overview of innate cellular recognition of HSV infection that leads to immune activation, and I discuss the implications of the known cell-host interactions. In addition, I discuss the use of innate stimulation to improve anti-HSV treatment and vaccine response and I discuss future research aims.

Adenoviral load diagnostics by quantitative polymerase chain reaction: techniques and application

Abstract: SUMMARY Human adenoviruses (HAdV) can cause fatal complications such as disseminated disease especially in a post-transplant setting. With conventional methods, disseminated HAdV disease could only be diagnosed with delay. Quantification of the HAdV load by real-time PCR in peripheral blood promised to solve this diagnostic dilemma. Here we review the development, applications and significance of quantitative HAdV PCR. The high genetic divergence of the 56 HAdV types was a major obstacle for developing a quantitative HAdV PCR covering all types. Several protocols focused either on a few, probably predominating types or tried to detect all known HAdV types by using a bundle of assays or a few multiplexed PCRs. Alternatively, generic quantitative real-time HAdV PCR protocols using primer and probe consensus sequences have been designed, providing considerable reduction of costs and hands-on time. Application of HAdV load testing by several studies on stem cell transplant (SCT) recipients indicated that rapidly increasing HAdV blood loads as well as high HAdV DNAemia (e.g. >104 copies/ml) are predictive for disseminated HAdV disease although a universal threshold value has not yet been established. HAdV load testing has been implemented for systematic screening of SCT patients permitting early diagnosis, pre-emptive treatment initiation and monitoring of antiviral therapy. However, further investigations are required to validate proposed virus load thresholds. Moreover, other applications of quantitative HAdV PCR, such as the diagnosis of localized HAdV disease, the analysis of environmental samples and monitoring of gene therapy with adenoviral vectors will be addressed in this review. Copyright © 2011 John Wiley & Sons, Ltd.

The race for interferon‐free HCV therapies: a snapshot by the spring of 2012

Abstract: After a decade of having been the standard of care (SOC) for the treatment of chronic HCV infection, PEGylated IFN (combined with ribavirin) is now at the verge of being complemented and then replaced by a combination of new DAAs and even some compounds interacting with host cell factors. Principal targets for the direct-acting antivirals (DAAs) are the protease NS3/4A, the protein NS5A, and the RNA-dependent RNA polymerase NS5B, which offers at least two target sites, the catalytic domain for nucleos(t)ides and several non-catalytic (allosteric) domains for the non-nucleoside type of NS5B inhibitors. Two PIs have already been approved, but many more NS3/4A, NS5A, and NS5B (up to 40!) inhibitors are in (pre)clinical development. The abundance of candidate anti-HCV drugs will, on the one hand, speed up their development but, on the other hand, complicate the choice of the most appropriate drug combination(s).

The ongoing pursuit of a prophylactic HSV vaccine.

Abstract: SUMMARY HSV is among the most common human pathogens in the world. It is known to cause painful, persistent skin lesions, while also being the most common cause of fatal non-epidemic encephalitis as well as the leading cause of corneal blindness. The development of prophylactic vaccines could substantially reduce global health problems associated with HSV. So far, HSV vaccine strategies have shown noticeable efficacy in early development during preclinical phases but remained unsuccessful or unproven in human trials. New understanding of how the immune system mounts a defence against HSV offers practical strategies for vaccine development. A number of promising vaccine candidates are currently awaiting clinical development or already undergoing clinical testing. Therefore, this is a suitable time to assess the progress of HSV vaccine development and consider existing challenges and future improvements needed to achieve an effective prophylactic HSV vaccine. Copyright © 2012 John Wiley & Sons, Ltd.

The contribution of different prion protein types and host polymorphisms to clinicopathological variations in Creutzfeldt–Jakob disease

Abstract: SUMMARY Creutzfeldt–Jakob disease is a fatal neurodegenerative disease that primarily affects the central nervous system. In this respect, it can be considered alongside the more frequently occurring neurodegenerative diseases, such as Alzheimer's disease. Creutzfeldt–Jakob disease is perhaps the paradigmatic protein misfolding disorder, so comparisons between the mechanisms involved in Creutzfeldt–Jakob disease and other neurodegenerative diseases associated with protein misfolding (such as the tauopathies and synucleinopathies) may also be informative. Like many of these diseases, Creutzfeldt–Jakob disease occurs sporadically or can, more rarely, be associated with mutations. However, Creutzfeldt–Jakob disease can also be acquired and is experimentally transmissible. These properties have had profound public health implications and made the disease of interest to virologists, in addition to those interested in protein misfolding disorders and neurodegeneration. The possible causes for the pronounced phenotypic variation among different forms of Creutzfeldt–Jakob disease are beginning to become understood, and these appear to depend in large measure on the genetics of the host (specifically the sequence of the prion protein gene, PRNP) and the epigenetic aspects of the agent (thought to be a misfolded and aggregated form of the PRNP gene product, termed a prion). This review will examine whether this model in its present form has sufficient complexity and subtlety to account for the clinicopathological variation evident in Creutzfeldt–Jakob disease and will outline the ways in which a more complete and informative molecular definition of human prions are currently being sought. Copyright © 2012 John Wiley & Sons, Ltd.

The type I interferon response during viral infections: a "SWOT" analysis.

Abstract: The type I interferon (IFN) response is a strong and crucial moderator for the control of viral infections. The strength of this system is illustrated by the fact that, despite some temporary discomfort like a common cold or diarrhea, most viral infections will not cause major harm to the healthy immunocompetent host. To achieve this, the immune system is equipped with a wide array of pattern recognition receptors and the subsequent coordinated type I IFN response orchestrated by plasmacytoid dendritic cells (pDCs) and conventional dendritic cells (cDCs). The production of type I IFN subtypes by dendritic cells (DCs), but also other cells is crucial for the execution of many antiviral processes. Despite this coordinated response, morbidity and mortality are still common in viral disease due to the ability of viruses to exploit the weaknesses of the immune system. Viruses successfully evade immunity and infection can result in aberrant immune responses. However, these weaknesses also open opportunities for improvement via clinical interventions as can be seen in current vaccination and antiviral treatment programs. The application of IFNs, Toll-like receptor ligands, DCs, and antiviral proteins is now being investigated to further limit viral infections. Unfortunately, a common threat during stimulation of immunity is the possible initiation or aggravation of autoimmunity. Also the translation from animal models to the human situation remains difficult. With a Strengths-Weaknesses-Opportunities-Threats ("SWOT") analysis, we discuss the interaction between host and virus as well as (future) therapeutic options, related to the type I IFN system.

Potential strategies and biosafety protocols used for dual‐use research on highly pathogenic influenza viruses

Abstract: Influenza A viruses (IAVs), particularly the highly pathogenic avian influenza H5N1, have posed a substantial threat to public health worldwide. Although the laboratory generation of the mutant influenza virus H5N1 with airborne transmissibility among mammals, which has been considered as a dual-use research, may benefit the development of effective vaccines and therapeutics against the emerging infectious agents, it may also pose threats to national biosecurity, laboratory biosafety, and/or public health. This review introduces the classification and characterization of IAVs, pinpoints historic pandemics and epidemics caused by IAVs, emphasizes the significance and necessity of biosafety, summarizes currently established biosafety-related protocols for IAV research, and provides potential strategies to improve biosafety protocols for dual-use research on the highly pathogenic avian influenza viruses and other emerging infectious agents.

Norovirus: tribulation and possible trial

Abstract: Winter is here and with it is norovirus. This perennial visitor brings major disruption to the work of closed communities, including hospitals, where it causes hypertension and dyspepsia in bed managers who see their targets for admitting patients for treatment receding as wards are closed. Norovirus is clearly a major disruptor to modern hospitals, incurring substantial costs in terms of staff time and additional cleaning. So what can be done to mitigate its effects? Norovirus was first identified in 1972 when a 27nm particle was seen by electron microscopy during investigation of an outbreak of gastroenteritis[1]. The affected school was in Norwalk, Ohio and gave the virus its original name, subsequently truncated to norovirus. It is a member of the Caliciviridae whose single-stranded RNA positive strand genome contains three open reading frames, the second of which encodes the major capsid protein. The pathogenesis produces reduced villus surface area of the duodenum and jejunum, but not the stomach, accompanied by an inflammatory infiltrate of perforin-positive cytotoxic T-lymphocytes[2,3]. There is active anion secretion as well as a leak flux component to the diarrhoea together with a possible autonomic stimulation of the central vomiting centre[2,3]. The resulting contamination of the environment with a hardy virus that is shed at a high viral load but has a low infectious dose and is difficult to disinfect explains its persistence[4]. Inpatients in modern hospitals are quite likely to be elderly now that many procedures are performed as day cases in patients who are fit enough to tolerate this. The elderly often have multiple medical problems needing longer hospital stay and are generally less able to clean up their body excretions, thereby helping to perpetuate any outbreak once it has started. Control of this infection at the community level would be ideal, but the development of vaccines against norovirus is in its infancy[5,6]. In fact, an influential early paper in the New England Journal of Medicine showed that some volunteers were

A watershed in clinical outcomes of human infections with highly pathogenic H5N1 avian influenza viruses: lessons from case-management in Egypt.

Abstract: Egypt confirmed its first case ofH5N1 virus infection in domestic poultry on 17 February 2006, and its first case of human infection on 17 March 2006 [1]. Since then, human as well as poultry infections have continued unabated. According to the World Health Organization (WHO), there have been 168 confirmed human cases in Egypt as of 27 August 2012, with 60 fatalities. The fatality rate has been quite high, reaching 35.7%, although this is significantly lower than the worldwide average of 59.0% (358 deaths/ 607 cases) as of 6 July 2012. Before the start of the epidemic, the government convened ameeting of its SupremeNationalCommittee to formulate a plan to deal with H5N1 infections in poultry and humans. The meeting was headed by the Minister of Health and included people from relevant ministries and representatives from the WHO and Food and Agriculture Organization [1]. The overarching goals of the National Strategy formulated by the committee are to contain the infection in poultry, minimize human exposure and infection, ensure strong social mobilization, and prepare for the event of a pandemic [1]. The followingmeasureswere put into place for the management of human cases [1]. First, suspected cases are referred to the nearest hospital able to deal with chest problems or fever, and antiviral therapy starts at admission.At the same time, a smear sample is taken and sent to the referral lab. Therefore, early hospitalization and concomitant antiviral prescription come first, with diagnosis coming next (5 million doses of oseltamivir were stockpiled for this reason). Second, suspected cases are referred to an identified referral hospital upon confirmation that the sample contains H5N1 or when the signs are severe. The identified referral hospitals are fully equipped with ventilation and other necessary facilities. Finally, another sample is taken following recovery and if negative for H5N1 RNA, the case is discharged from the hospital. Egypt has received global recognition for its transparency in releasing information on the epidemics

Editorial: baby boomers and virology.

Abstract: The chronically depressing financial news is making people look for scapegoats, and some have focused on the baby boomers. This term was coined by Landon Jones and is defined as those who were born in the 18 years after the end of the Second World War [1]. Too young to have personal memories of the hardships of that conflagration, they grew up expecting the world to improve with time, fuelled by the post-war economic boom. The current generation of young adults looks back and marvels at the benefits our generation had. We received education provided by the state; there was then an unprecedented expansion of universities to bring higher education within the reaches of the masses; we were never conscripted into the Armed Forces; we enjoyed unfettered sexual liberation in the 1960s without having to consider the problem of AIDS; the government provided state guaranteed pensions; our mortgage costs were subsidised by the government, and the resulting massive growth in the value of our houses provided a substantial financial nest egg. Having had all this largesse showered upon us in the past, we are now charged with selfishly benefiting from improved survival by hanging onto our houses and refusing to pass the assets onto the younger generation. No wonder that Baby Boomers are accused of thinking of themselves as a special generation [1]. None of the critics suggests that every baby boomer benefited from all of these things, or succumbed to every temptation on the list. Indeed, the contents of the list will vary according to the country people live in. But the critics do have a point; our generation has been showered with benefits out of all proportion to those the current generation will receive. Is there anything to lighten the impression that we have taken everything and left nothing behind?

Controversy over bird flu.

Abstract: When I editorialised 4 years ago [1] that bird flu showed no signs of acquiring mutations that would allow it to transmit readily from person-to-person, I did not anticipate that some of our colleagues would subsequently be accused publicly of helping the virus to achieve this milestone. To start with the facts, one laboratory in the USA and another in the Netherlands have altered H5N1 influenza and shown that it is transmissible between ferrets by the airborne route. The laboratory in the USA inserted the gene for the haemagglutinin of H5 into a pandemic H1N1 strain whereas the Dutch laboratory passaged an H5N1 virus 10 times in ferrets to select a virus with five mutations which, in combination, confer transmissibility [2]. Although both viruses are transmissible, only the example in Holland produced disease in ferrets. The two papers describing this work are in press with Nature and Science, but will be published without important details, because the USA National Science Advisory Board for Biosecurity requested redaction of specific facts about methodology and results when the authors and journals sought their advice. As background, this committee is just advisory. It was set up in response to the 2001 anthrax letters in the USA to seek a middle ground between those who wanted to regulate experiments as well as limit the publication of dual use research and scientists who wanted open publication. Self-regulation with this board of scientists to advise on specific cases was the compromise [3]. The authors and the journals will agree to the redactions provided that a system is created to give access to the missing details to scientists who need to know [2]. It would be difficult for a committee in one country to perform this task, so all eyes are on WHO, which already has an international smallpox research panel. This unprecedented request for redaction triggered extensive controversy with strong opinions from many sides, culminating in a voluntary 60 day moratorium on further laboratory work with these viruses signed by all 39 Principal Investigators who conduct this type of research [4]. A meeting held 16–17 February