Showing papers in "Reviews in Medical Virology in 2013"

Hantavirus infections in Europe and their impact on public health.

Abstract: Hantaviruses (genus Hantavirus, family Bunyaviridae) are enveloped tri-segmented negative-stranded RNA viruses each carried by a specific rodent or insectivore host species. Several different hantaviruses known to infect humans circulate in Europe. The most common is Puumala (PUUV) carried by the bank vole; another two important, genetically closely related ones are Dobrava-Belgrade (DOBV) and Saaremaa viruses (SAAV) carried by Apodemus mice (species names follow the International Committee on Taxonomy of Viruses nomenclature). Of the two hantaviral diseases, hemorrhagic fever with renal syndrome (HFRS) and hantaviral cardiopulmonary syndrome, the European viruses cause only HFRS: DOBV with often severe symptoms and a high case fatality rate, and PUUV and SAAV more often mild disease. More than 10,000 HFRS cases are diagnosed annually in Europe and in increasing numbers. Whether this is because of increasing recognition by the medical community or due to environmental factors such as climate change, or both, is not known. Nevertheless, in large areas of Europe, the population has a considerable seroprevalence but only relatively few HFRS cases are reported. Moreover, no epidemiological data are available from many countries. We know now that cardiac, pulmonary, ocular and hormonal disorders are, besides renal changes, common during the acute stage of PUUV and DOBV infection. About 5% of hospitalized PUUV and 16%-48% of DOBV patients require dialysis and some prolonged intensive-care treatment. Although PUUV-HFRS has a low case fatality rate, complications and long-term hormonal, renal, and cardiovascular consequences commonly occur. No vaccine or specific therapy is in general use in Europe. We conclude that hantaviruses have a significant impact on public health in Europe.

Comparing HIV-1 and HIV-2 infection: Lessons for viral immunopathogenesis.

Abstract: HIV-1 and HIV-2 share many similarities including their basic gene arrangement, modes of transmission, intracellular replication pathways and clinical consequences: both result in AIDS. However, HIV-2 is characterised by lower transmissibility and reduced likelihood of progression to AIDS. The underlying mechanistic differences between these two infections illuminate broader issues of retroviral pathogenesis, which remain incompletely understood. Comparisons between these two infections from epidemiological, clinical, virologic and immunologic viewpoints provide a basis for hypothesis generation and testing in this 'natural experiment' in viral pathogenesis. In terms of epidemiology, HIV-2 remains largely confined to West Africa, whereas HIV-1 extends worldwide. Clinically, HIV-2 infected individuals seem to dichotomise, most remaining long-term non-progressors, whereas most HIV-1 infected individuals progress. When clinical progression occurs, both diseases demonstrate very similar pathological processes, although progression in HIV-2 occurs at higher CD4 counts. Plasma viral loads are consistently lower in HIV-2, as are average levels of immune activation. Significant differences exist between the two infections in all components of the immune system. For example, cellular responses to HIV-2 tend to be more polyfunctional and produce more IL-2; humoral responses appear broader with lower magnitude intratype neutralisation responses; innate responses appear more robust, possibly through differential effects of tripartite motif protein isoform 5 alpha. Overall, the immune response to HIV-2 appears more protective against disease progression suggesting that pivotal immune factors limit viral pathology. If such immune responses could be replicated or induced in HIV-1 infected patients, they might extend survival and reduce requirements for antiretroviral therapy.

The apparent paradox of maternal seropositivity as a risk factor for congenital cytomegalovirus infection: a population-based prediction model.

Abstract: Because maternal seropositivity for CMV is associated with substantial protection against congenital CMV infection, prevention measures have focused mainly on seronegative pregnant women for decades. However, population-wide insight in the contribution of nonprimary infection (reactivation and/or re-infection with a different strain) on the most common sequela, hearing loss, is missing. A population-based prediction model was developed to estimate the proportion of congenital CMV-related hearing loss resulting from nonprimary maternal infection. Incorporated was a meta-analysis of the risk of hearing loss, calculating pooled proportions of children with hearing loss after nonprimary and primary infection. Subsequently, the model was applied for worldwide present population seroprevalences (range 30-95%). It was estimated that, for all population seroprevalences, nonprimary maternal infections are responsible for the majority of congenital CMV infections. This proportion increased with seroprevalence, ranging from 57% (95%CI 24-85%) to 96% (95% CI 88-99%) for seroprevalences of 30% to 95%. Our meta-analysis (six reports) showed that the risk of hearing loss after nonprimary infection was 11% (28/253 children, 95% CI 7-15%) versus 13% (50/385 children, 95% CI 10-16%) after primary infection. Incorporating this risk into our model, we estimated that nonprimary infections also accounted for the majority of CMV-related hearing loss. This proportion ranged from 53% (95% CI 13-86%) to 95% (95% CI 62-99%) for seroprevalences of 30% to 95%. Our data underline the worldwide contribution of nonprimary infections in causing CMV-related hearing loss. These results imply that prevention research such as vaccine and hygiene studies should not only be directed at seronegative but also seropositive pregnant women. © 2013 John Wiley & Sons, Ltd.

Adeno-associated virus (AAV) vectors in gene therapy: immune challenges and strategies to circumvent them

Abstract: SUMMARY AAV-based gene transfer protocols have shown remarkable success when directed to immune-privileged sites such as for retinal disorders like Lebers congenital amaurosis. In contrast, AAV-mediated gene transfer into liver or muscle tissue for diseases such as hemophilia B, α1 anti-trypsin deficiency and muscular dystrophy has demonstrated a decline in gene transfer efficacy over time. It is now known that in humans, AAV triggers specific pathways that recruit immune sensors. These factors initiate an immediate reaction against either the viral capsid or the vector encoded protein as part of innate immune response or to produce a more specific adaptive response that generates immunological memory. The vector-transduced cells are then rapidly destroyed due to this immune activation. However, unlike other viral vectors, AAV is not immunogenic in murine models. Its immunogenicity becomes apparent only in large animal models and human subjects. Moreover, humans are natural hosts to AAV and exhibit a high seroprevalence against AAV vectors. This limits the widespread application of AAV vectors into patients with pre-existing neutralising antibodies or memory T cells. To address these issues, various strategies are being tested. Alternate serotype vectors (AAV1-10), efficient expression cassettes, specific tissue targeting, immune-suppression and engineered capsid variants are some approaches proposed to minimise this immune stimulation. In this review, we have summarised the nature of the immune response documented against AAV in various pre-clinical and clinical settings and have further discussed the strategies to evade them. Copyright © 2013 John Wiley & Sons, Ltd.

Genome guardian p53 and viral infections

Abstract: Because virus infections elicit various cellular responses that inhibit viral replication and growth, viruses must intervene to attenuate antiviral measures in order to thrive. The genome guardian p53 plays a central part not only in DNA damage responses, inducing cell cycle arrest or apoptosis, but also in the innate host immune control of viral infections by orchestrating diverse signaling pathways originating from many different cellular receptors and sensors. Many viruses have acquired sophisticated mechanisms to regulate p53 functions by deploying subversive proteins and modulating its post-transcriptional status. In this review, we overview the mechanisms by which DNA and RNA viruses manage p53 signaling in favor of their continued survival.

Noroviruses and histo‐blood groups: the impact of common host genetic polymorphisms on virus transmission and evolution

Abstract: Noroviruses (NoVs) are recognized as a leading cause of human gastroenteritis worldwide. Infection occurs following the ingestion of contaminated food or, most often, through direct contact from person to person. However, not all individuals are equally sensitive to these viruses. Indeed, NoVs use glycans of the ABH and Lewis histo-blood group antigen family (HBGAs) as attachment factors. At the epithelial level, the synthesis of these HBGAs requires the action of several glycosyltransferases that are encoded by the ABO, FUT2, and FUT3 genes. The combined polymorphism at these three loci dictates sensitivity to NoV infection because the attachment profile to these glycans varies among strains. Structural analysis of the capsid protein interaction with HBGAs reveals distinct modes of binding for strains of genogroups I and II but high conservation within each genogroup, whereas minor amino acid changes are sufficient to generate modifications of HBGA-binding specificities or affinities. Such modifications therefore induce changes in the spectrum of susceptible individuals. Studies of NoV-HBGA interactions together with phylogenetic analyses and the epidemiologic survey of strains indicate that NoV transmission and evolution depend on both the establishment of herd immunity and the genetic resistance of many individuals, which confers herd innate protection by restricting NoV circulation.

Immunity and immune response, pathology and pathologic changes: progress and challenges in the immunopathology of yellow fever†

Abstract: Yellow fever is a viral hemorrhagic fever, which affects people living in Africa and South America and is caused by the yellow fever virus, the prototype species in the Flavivirus genus (Flaviviridae family). Yellow fever virus infection can produce a wide spectrum of symptoms, ranging from asymptomatic infection or oligosymptomatic illness to severe disease with a high fatality rate. In this review, we focus in the mechanisms associated with the physiopathology of yellow fever in humans and animal models. It has been demonstrated that several factors play a role in the pathological outcome of the severe form of the disease including direct viral cytopathic effect, necrosis and apoptosis of hepatocyte cells in the midzone, and a minimal inflammatory response as well as low-flow hypoxia and cytokine overproduction. New information has filled several gaps in the understanding of yellow fever pathogenesis and helped comprehend the course of illness. Finally, we discuss prospects for an immune therapy in the light of new immunologic, viral, and pathologic tools.

Epidemiology and management of chronic hepatitis E infection in solid organ transplantation: a comprehensive literature review

Abstract: Hepatitis E virus (HEV) infection has emerged as a global public health issue. Although it often causes an acute and self-limiting infection with low mortality rates in the western world, it bears a high risk of developing chronic hepatitis in immunocompromised patients with substantial mortality rates. Organ transplant recipients who receive immunosuppressive medication to prevent rejection are thought to be the main population at risk for chronic hepatitis E. Therefore, there is an urgent need to properly evaluate the clinical impact of HEV in these patients. This article aims to review the prevalence, infection course, and management of HEV infection after solid organ transplantation by performing a comprehensive literature review. In addition, an in-depth emphasis of this clinical issue and a discussion of future development are also presented.

Effect of maintenance immunosuppressive drugs on virus pathobiology: evidence and potential mechanisms

Abstract: Recent evidence suggesting a potential anti-CMV effect of mTORis is of great interest to the transplant community. However, the concept of an immunosuppressant with antiviral properties is not new, with many accounts of the antiviral properties of several agents over the years. Despite these reports, to date, there has been little effort to collate the evidence into a fuller picture. This manuscript was developed to gather the evidence of antiviral activity of the agents that comprise a typical immunosuppressive regimen against viruses that commonly reactivate following transplant (HHV1 and 2, VZV, EBV, CMV and HHV6, 7, and 8, HCV, HBV, BKV, HIV, HPV, and parvovirus). Appropriate immunosuppressive regimens posttransplant that avoid acute rejection while reducing risk of viral reactivation are also reviewed. The existing literature was disparate in nature, although indicating a possible stimulatory effect of tacrolimus on BKV, potentiation of viral reactivation by steroids, and a potential advantage of mammalian target of rapamycin (mTOR) inhibition in several viral infections, including BKV, HPV, and several herpesviruses.

Serological cross-reactivity between human polyomaviruses.

Abstract: SUMMARY Until 2006, BKPyV and JCPyV were the only known human polyomaviruses. A third polyomavirus, simian virus 40 whose natural host is the macaque was accidently introduced into man because of contaminated poliovirus vaccines, although there is epidemiological evidence that SV40 may be transmitted between man independently from contaminated vaccines. Since 2007, 10 new human polyomaviruses have been identified: KIPyV, WUPyV, Merkel cell polyomavirus, trichodysplasia spinulosa-associated polyomavirus, and human polyomaviruses 6, 7, 9, 10, STL, and 12. Moreover, the DNA of the monkey lymphotropic polyomavirus has been amplified from human peripheral blood. Seroepidemiological studies frequently based on the presence of antibodies against the major capsid protein VP1 or virus-like particles indicate that most human adults have been exposed to many, if not all, human polyomaviruses. However, because of the high amino acid sequence identity between VP1 of some human polyomaviruses, cross-reactivity of antibodies is occasionally observed. In addition, human sera possess reactivity against VP1 of polyomaviruses from other species, suggesting serological cross-reaction with known or closely related, yet unidentified human polyomaviruses and/or the possibility of zoonotic transmission. Thus, current serological results should be interpreted with caution, and controls excluding cross-reactivity with other polyomaviruses are required. Copyright © 2013 John Wiley & Sons, Ltd.

Glycoprotein targeted therapeutics: a new era of anti-herpes simplex virus-1 therapeutics.

Abstract: Herpes simplex virus type-1 (HSV-1) is among the most common human pathogens worldwide. Its entry into host cells is an intricate process that relies heavily on the ability of the viral glycoproteins to bind host cellular proteins and to efficiently mediate fusion of the virus envelope with the cell membrane. Acquisition of HSV-1 results in a lifelong latent infection. Because of the cycles of reactivation from a latent state, much emphasis has been placed on the management of infection through the use of DNA synthesis inhibitors. However, new methods are needed to provide more effective treatment at earlier phases of the viral infection and to prevent the development of drug resistance by the virus. This review outlines the infection process and the common therapeutics currently used against the fundamental stages of HSV-1 replication and fusion. The remainder of this article will focus on a new approach for HSV-1 infection control and management, the concept of glycoprotein-receptor targeting.

Tissue dendritic cells as portals for HIV entry

Abstract: Dendritic cells (DCs) are found at the portals of pathogen entry such as the mucosal surfaces of the respiratory, gastrointestinal and genital tracts where they represent the first line of contact between the immune system and the foreign invaders. They are found throughout the body in multiple subsets where they express unique combinations of C-type lectin receptors to best aid them in detection of pathogens associated with their anatomical location. DCs are important in the establishment in HIV infection for two reasons. Firstly, they are one of the first cells to encounter the virus, and the specific interaction that occurs between these cells and HIV is critical to HIV establishing a foothold infection. Secondly and most importantly, HIV is able to efficiently transfer the virus to its primary target cell, the CD4(+) T lymphocyte, in which it replicates explosively. Infection of CD4(+) T lymphocytes via DCs is far more efficient than direct infection. This review surveys the various DCs subsets found within the human sexual mucosa and their interactions with HIV. Mechanisms of HIV uptake are discussed as well as how the virus then traffics through the DC and is transferred to T cells. Until recently, most research has focussed on vaginal transmission despite the increased transmission rate associated with anal intercourse. Here, we also discuss recent advances in our understanding of HIV transmission in the colon.

BamHI-A rightward frame 1, an Epstein–Barr virus-encoded oncogene and immune modulator

Abstract: Epstein–Barr virus (EBV) causes several benign and malignant disorders of lymphoid and epithelial origin. EBV-related tumors display distinct patterns of viral latent gene expression, of which the BamHI-A rightward frame 1 (BARF1) is selectively expressed in carcinomas, regulated by cellular differentiation factors including ΔNp63α. BARF1 functions as a viral oncogene, immortalizing and transforming epithelial cells of different origin by acting as a mitogenic growth factor, inducing cyclin-D expression, and up-regulating antiapoptotic Bcl-2, stimulating host cell growth and survival. In addition, secreted hexameric BARF1 has immune evasive properties, functionally corrupting macrophage colony stimulating factor, as supported by recent functional and structural data. Therefore, BARF1, an intracellular and secreted protein, not only has multiple pathogenic functions but also can function as a target for immune responses. Deciphering the role of BARF1 in EBV biology will contribute to novel diagnostic and treatment options for EBV-driven carcinomas. Herein, we discuss recent insights on the regulation of BARF1 expression and aspects of structure-function relating to its oncogenic and immune suppressive properties. © 2013 The Authors. Reviews in Medical Virology published by John Wiley & Sons, Ltd.

Viral ocular manifestations: a broad overview.

Abstract: The viruses able to affect the eye are taxonomically diverse, ranging from double-stranded DNA viruses, to single stranded RNA viruses, to retroviruses. Any part of the eye may be affected, frequently producing blepharitis, conjunctivitis, keratitis, uveitis, cataract and retinitis. The more common ocular viral infections include the Herpesviruses such as HSV-1, VZV and CMV. The HIV pandemic is placing a serious burden on ophthalmology clinics, particularly in sub-Saharan Africa as the number of viral ocular diseases is increasing. In particular, CMV retinitis is becoming more prevalent where antiretroviral therapy is not available and is replaced by immune-recovery uveitis where antiretrovirals are given. This review aims to improve knowledge of the common viral ocular diseases, their diagnosis and management, as well as the fairly uncommon viral ocular diseases that may also cause considerable morbidity.

Sphingosine kinase 1 in viral infections.

Abstract: Sphingosine kinase 1 (SphK1) is an enzyme that phosphorylates the lipid sphingosine to generate sphingosine-1-phosphate (S1P). S1P can act intracellularly as a signaling molecule and extracellularly as a receptor ligand. The SphK1/S1P axis has well-described roles in cell signaling, the cell death/survival decision, the production of a pro-inflammatory response, immunomodulation, and control of vascular integrity. Agents targeting the SphK1/S1P axis are being actively developed as therapeutics for cancer and immunological and inflammatory disorders. Control of cell death/survival and pro-inflammatory immune responses is central to the pathology of infectious disease, and we can capitalize on the knowledge provided by investigations of SphK1/S1P in cancer and immunology to assess its application to selected human infections. We have herein reviewed the growing literature relating viral infections to changes in SphK1 and S1P. SphK1 activity is reportedly increased following human cytomegalovirus and respiratory syncytial virus infections, and elevated SphK1 enhances influenza virus infection. In contrast, SphK1 activity is reduced in bovine viral diarrhea virus and dengue virus infections. Sphingosine analogs that modulate S1P receptors have proven useful in animal models in alleviating influenza virus infection but have shown no benefit in simian human immunodeficiency virus and lymphocytic choriomeningitis virus infections. We have rationalized a role for SphK1/S1P in dengue virus, chikungunya virus, and Ross River virus infections, on the basis of the biology and the pathology of these diseases. The increasing number of effective SphK1 and S1P modulating agents currently in development makes it timely to investigate these roles with the potential for developing modulators of SphK1 and S1P for novel anti-viral therapies.

Hepatitis E: current status.

Abstract: Acute hepatitis E is a very common disease in developing countries, to the point that, according to World Health Organization estimates, one third of the world's population has been exposed to HEV. It also causes outbreaks in refugee camps or after natural disasters such as floods or earthquakes. Sporadic cases of acute hepatitis have been observed in practically all European countries and other developed geographical areas, not only in travelers from endemic countries but also in people with no risk factors. But, lately, new aspects of this infection are appearing in industrialized countries such as the possibility of the disease becoming chronic in transplant patients, the immunocompromised in general, and even in patients with previous liver disease who are immunocompetent. In this comprehensive review, we summarize the current knowledge on HEV infection.

The ubiquitin-proteasome system in positive-strand RNA virus infection.

Abstract: Positive-stranded RNA viruses, like many other viruses, have evolved to exploit the host cellular machinery to their own advantage. In eukaryotic cells, the ubiquitin-proteasome system (UPS) that serves as the major intracellular pathway for protein degradation and modification plays a crucial role in the regulation of many fundamental cellular functions. A growing amount of evidence has suggested that the UPS can be utilized by positive-sense RNA viruses. The UPS eliminates excess viral proteins that prevent viral replication and modulates the function of viral proteins through post-translational modification mediated by ubiquitin or ubiquitin-like proteins. This review will discuss the current understanding of how positive RNA viruses have evolved various mechanisms to usurp the host UPS to modulate the function and stability of viral proteins. In addition to the pro-viral function, UPS-mediated viral protein degradation may also constitute a host defense process against some positive-stranded RNA viral infections. This issue will also be discussed in the current review.

Pandemic influenza A(H1N1) 2009 virus in pregnancy

Abstract: Two hundred fourteen abstracts and 87 full texts regarding pregnant women infected with pandemic influenza A(H1N1) 2009 virus were systematically reviewed by using a PubMed search and assessing pandemic, clinical, laboratory test, vaccine, and control experiences. Both policy and health education were excluded. This review counted the total number of pregnant cases from different countries and analyzed their epidemic features, including trimester distribution, morbidity, hospitalization, intensive care unit admissions, maternal mortality, underlying diseases, complications, high-risk factors for death, pregnancy outcome, and clinical symptoms compared with the previous pandemic seasonal influenza A/H1N1 as compared with the general population. Early identification and treatment were the most important factors in different countries and areas examined. The vaccine and antiviral drugs that have been the most efficient means to control the novel virus appear to be safe but require more extensive study. In the future, the focus should be placed on understanding vertical transmission and the severe mechanisms.

Current knowledge and systematic review of viruses associated with Crohn's disease

Abstract: The aetiology of Crohn's disease (CD) is currently unknown A viral trigger was proposed more than 40 years ago and has been the focus of many investigations We summarised the current literature surrounding the association between viruses and CD and conducted a systematic review of all studies investigating this association quantitatively Studies were identified by searching for 13 specific virus names or the general term 'virus' and 'Crohn's disease' in search engines PubMed and OVID A total of 1315 studies were identified, of which 78 studies had a laboratory result Of the 78, 46 case-control studies met all the inclusion criteria for forest plot analysis The most common viruses studied were EBV, CMV and measles virus (MV) Forest plot analysis for each virus was carried out (fitted using random effects) and identified evidence of an association between CD and CMV (risk ratio [RR] 1602, 95% confidence interval [CI] 1069 to 2400) with some suggestion that EBV may also be associated with CD (RR 1366, 95% CI 0996 to 1873) However, there was evidence of large heterogeneity in the results from the identified studies for EBV There was little evidence of an association with CD for MV, human herpes virus 6, human herpes virus 8, human simplex virus, varicella-zoster virus, mumps virus, Rubella virus, rotavirus, norovirus and adenovirus There is still some question around whether CD is associated with the presence of a currently known virus

Recent developments with live-attenuated recombinant paramyxovirus vaccines.

Abstract: There is no vaccine currently approved for paramyxovirus-induced respiratory diseases in humans, despite their major clinical importance. We review the development and evaluation of new vaccine strategies based on live-attenuated chimeric and recombinant vaccines against human respiratory syncytial virus, human metapneumovirus and human parainfluenza viruses types 1 to 3, which are significant causes of upper and lower tract respiratory diseases. Most promising strategies are based on virus attenuation through (i) mutations in key genes involved in replication; (ii) deletion of accessory genes; or (iii) the use of a corresponding animal viral vector, such as bovine parainfluenza type 3 and Sendai virus, as a background for the expression of a viral glycoprotein. Indeed, the fusion (F), or attachment (HN/H/G) glycoproteins are the most immunogenic antigens in paramyxoviruses. For each strategy, we will review the immunogenicity (increase in neutralising antibody titres) and the protection conferred by the most promising recombinant vectored vaccines and list ongoing clinical trials. We will conclude by discussing the most important challenges regarding the introduction of such vaccines into immunisation programmes.

Contribution of dendritic cells to measles virus induced immunosuppression.

Abstract: SUMMARY Measles virus (MV) remains an important pathogen in children worldwide. The morbidity and mortality of MV is associated with severe immune suppression. Dendritic cells (DCs) were identified as initial target cells in vivo, and DCs were efficiently infected by MV in vitro. MV infection of DCs likely contributes to functional deficiency in these cells; therefore playing a role in MV-induced immunosuppression. DCs appeared to mature phenotypically; however, the ability of infected cells to stimulate T cells was compromised. Phenotypic maturation of infected immature DCs was partially controlled by IFN production; however, infected DCs also maintained markers of an immature phenotype such as the continued uptake of antigen and lack of expression of chemokine receptor CCR7. Furthermore, mature DCs did not appear to maintain phenotypic maturation following infection demonstrated by decreased MHC and co-stimulatory molecule expression. Several mechanisms of MV-induced DC dysfunction have been suggested, each likely contributing to the immunosuppressive effect of MV-infected DCs. Infected DCs responded aberrantly to secondary maturation stimuli such as CD40L or TLR4 stimulation. MV infection resulted in apoptosis in DC/T-cell cocultures, which may contribute to a reduced T-cell response. Additionally, the immunological synapse between infected DCs and T cells was compromised resulting in reduced T-cell interaction times and activation signaling. The mechanisms of MV contribution to DC dysfunction appear multifaceted and central to MV-induced immunosuppression. Published 2012. This article is a U.S. Government work and is in the public domain in the USA.

Unmasking the information encoded as structural motifs of viral RNA genomes: a potential antiviral target.

Abstract: RNA viruses show enormous capacity to evolve and adapt to new cellular and molecular contexts, a consequence of mutations arising from errors made by viral RNA-dependent RNA polymerase during replication. Sequence variation must occur, however, without compromising functions essential for the completion of the viral cycle. RNA viruses are safeguarded in this respect by their genome carrying conserved information that does not code only for proteins but also for the formation of structurally conserved RNA domains that directly perform these critical functions. Functional RNA domains can interact with other regions of the viral genome and/or proteins to direct viral translation, replication and encapsidation. They are therefore potential targets for novel therapeutic strategies. This review summarises our knowledge of the functional RNA domains of human RNA viruses and examines the achievements made in the design of antiviral compounds that interfere with their folding and therefore their function.

Virological and immunological mechanisms in the pathogenesis of human T-cell leukemia virus type 1.

Abstract: SUMMARY Human T-cell leukemia virus type 1 (HTLV-1) was the first retrovirus shown to cause human disease, such as adult T-cell leukemia and HTLV-1 associated myelopathy/tropic spastic paraparesis. HTLV-1 mainly infects CD4 T cells and deregulates their differentiation, function and homeostasis, which should contribute to the pathogenesis of HTLV-1, for example, inducing transformation of infected CD4 T cells and chronic inflammatory diseases. Therefore, not only virological approach but also immunological approach regarding CD4 T cells are required to understand how HTLV-1 causes related human diseases. This review focuses on recent advances in our understanding of the interaction between HTLV-1 and the main host cell, CD4 T cells, which should provide us some clue to the mechanisms of HTLV-1 mediated pathogenesis. Copyright © 2013 John Wiley & Sons, Ltd.

Letter in response to: Making the case: Married versus Separate models of alphaherpes virus anterograde transport in axons

Abstract: We are writing in response to a recent review: ‘Making the case: Married versus Separate models of alphaherpes virus anterograde transport in axons’, by Kratchmarov, Taylor and Enquist (July 16, 2012). This review compares evidence for theMarried (fully assembled, enveloped particles) versus Separate (unenveloped capsids)models of anterograde axonal transport for two alphaherpesviruses: the swine pseudorabies virus (PRV) and the human herpes simplex virus type 1 (HSV-1). The main thrust of this review is that the Married model of anterograde transport is certain for PRV, whereas with HSV-1, there is evidence for both models. The authors are strong proponents of the Married model and build a case that the major form of anterograde transport for HSV-1 also involves Married particles. They advocate for the use of live cell imaging of dual fluorescent viral recombinants, which they suggest produce more accurate information on whether capsids are undergoing transport as Separate versus Married particles, compared with static antibodystained and electron microscopy (EM) images. Although live cell imaging can be useful in these analyses, there are major disadvantages because the viral recombinants used are often defective in assembly. We would argue that antibody and EM studies produced a more accurate assessment of HSV-1 transport and suggest that there are quantitative (and qualitative) differences in the anterograde transport of HSV-1 versus PRV. Further, several of the arguments against the Separate transport model for HSV-1 were selective and, in some cases, imbalanced or inaccurate.

Emerging viral diseases in kidney transplant recipients

Abstract: SUMMARY Viruses are the most important cause of infections and a major source of mortality in Kidney Transplant Recipients (KTRs). These patients may acquire viral infections through exogenous routes including community exposure, donor organs, and blood products or by endogenous reactivation of latent viruses. Beside major opportunistic infections due to CMV and EBV and viral hepatitis B and C, several viral diseases have recently emerged in KTRs. New medical practices or technologies, implementation of new diagnostic tools, and improved medical information have contributed to the emergence of these viral diseases in this special population. The purpose of this review is to summarize the current knowledge on emerging viral diseases and newly discovered viruses in KTRs over the last two decades. We identified viruses in the field of KT that had shown the greatest increase in numbers of citations in the NCBI PubMed database. BKV was the most cited in the literature and linked to an emerging disease that represents a great clinical concern in KTRs. HHV-8, PVB19, WNV, JCV, H1N1 influenza virus A, HEV, and GB virus were the main other emerging viruses. Excluding HHV8, newly discovered viruses have been infrequently linked to clinical diseases in KTRs. Nonetheless, pathogenicity can emerge long after the discovery of the causative agent, as has been the case for BKV. Overall, antiviral treatments are very limited, and reducing immunosuppressive therapy remains the cornerstone of management. Copyright © 2012 John Wiley & Sons, Ltd.

Hepatitis B and C in liver transplantation: new strategies to combat the enemies.

Abstract: SUMMARY Hepatitis B immune globulin-free therapeutic regimens with a nucleos(t)ide analogue (NUC) or NUC combinations after liver transplantation (LT) are currently being investigated for their efficacy and safety as HBV re-infection prophylaxis in clinical studies. Recurrence rates differ among these studies as most of them are limited by a non-randomised study design, small sample size, lack of long-term data and varying time intervals for the switch from combined to purely virostatic prophylaxis. Post-transplant pre-emptive antiviral therapy with pegylated IFN and ribavirin is associated with low sustained virological response rates and was found to have no advantage over treatment of manifest HCV re-infection. Safety and efficacy of triple antiviral therapy including boceprevir or telaprevir in patients with manifest HCV re-infection are currently under investigation in clinical trials. Relevant drug interactions have been shown to occur during calcineurin inhibitor (CNI) and concomitant triple antiviral therapy, which vary with type of CNI and choice of HCV protease inhibitor. Newer direct-acting antivirals with lower or minimal toxicity, when used in combination with immunosuppressives, are worthy of further study in LT patients. This review focuses on hot topics in the management of hepatitis B and C patients before and after LT and offers a critical summarised selection of the corresponding relevant studies published in the current literature or presented at recent liver congresses. Copyright © 2012 John Wiley & Sons, Ltd.

Orphan viruses, orphan diseases: still the raw material for virus discovery

Abstract: This journal’s title specifies reviews of medical virology, and it is important not to lose sight of this, its primary purpose. The inter-relationship between virological research, clinical disease and public health should be at the heart of the journal’s contents. The viruses of humans are diverse, and the RNA viruses especially are unstable life forms on a continuing journey towards symbiosis with their host species. During this evolution, they may trade virulence for transmissibility, but they probably never establish complete harmony with their host. So, whenever a ‘new’ virus is isolated and is suspected of being a pathogen, it is important to ask what its range of virulence is, even if such questions may be difficult to answer comprehensively. It is now 60years since monolayer cell culture was first applied to the isolation and propagation of viruses. It soon uncovered a superfluity of isolates in human faecal extracts and throat swabs, many of themof uncertain pathogenicity. There was no doubt about the virulence of the three poliovirus types, nor of some other ‘enteroviruses’, such as the Coxsackie viruses that were pathogenic for mice and also associatedwith acute human illness; but there were other serologically distinct enteroviruses that seemed to be non-pathogenic both for humans and experimental animals. Only when the moment came that their occurrence coincided with local outbreaks of rash or other illness did their pathogenicity become apparent, and they were more closely investigated. At first, therefore, many enteroviruses were referred to as ECHO, that is, enterocytopathic orphan viruses, the term ‘orphan’ being applied because they lacked a parent disease. This term was, according to Gilbert Dalldorf, conceived by a group of pioneers of virus cell culture ‘in a moment of conviviality’ (Dalldorf, a New York pathologist, was the investigator who had previously shown that Coxsackie viruses caused paralysis in newborn mice but not in humans). Many so-called orphan viruses were subsequently linked to diseases. However, by the mid-1960s, the use of cell monolayers had become so routine in

Consensus is needed at a global level concerning dual-use research.

Abstract: Dual-use research in biomedical science is a longtermunresolved issue. Dual-use refers tomeritorious science that would benefit mankind but that might be misused, as with bioterrorism or nuclear warfare. The debates focus on the balance between advancement of science and promotion of biosecurity. In the past, there have beenmany dual-use research controversies in life science, such as the IL-4 superstrain mousepox [1], the de novo synthesis of polio virus [2], and the reconstruction of the 1918 Influenza virus [3]. In 2012, there again emerged heated debates on the publication of two studies on mutant H5N1 strains, a highly pathogenic avian influenza virus. Yoshihiro Kawaoko’s team created a hybrid virus with genes from both H5N1 and the H1N1 strains [4], while Ron Fouchier’s team created a newvirus with only fivemutations, using traditional passaging technology [5]; both viruses are highly transmissible via the airborne route among ferrets. The months-long scientific debate and controversy further highlights the importance of establishing a mechanism to guide and regulate dual-use research. In this issue, Du et al. have reviewed established biosafety-related protocols for influenzaA virus research and provide potential strategies to improve biosafety protocols for dual-use research on the highly pathogenic avian influenza viruses and other emerging infectious pathogens. Science may act as a double-edged sword. Nuclear science can be used in medicine and as an energy source but also represents a threat to humankind and the environment if it ismismanaged and misused. The nuclear bomb was used twice in war, but biological weapons were used many times during World War II [6]. Even though one should never underestimate the risk of bioterror, welldocumented bioterrorist attacks rarely occur with the notable exception of the 2001 anthrax attack [7]. Far more damage has been caused by lab accidents due to malpractice or faulty management in dual research on highly pathogenic organisms than has been caused by bioterrorism; these laboratory infections and leaks of various pathogens have

Editorial: an anniversary and a new member of the family

Abstract: How rapidly a decade flashes by! Was it really 10 years ago when we heard, bit by bit, about a new disease with frightening, even apocalyptic potential? When tales of heroism were supplanted, temporarily, by fears of bioterrorism as the ominously numbered room 911 of the Metropole Hotel accommodated the first case to come to widespread attention in the West? The true origin turned out to be nature, not man, acting as a malign force to create a novel pathogen. And now, we have another virus from the same family affecting the same body system as the one from a decade ago. Will it stay localised to small pockets of infection or cause another pandemic like its cousin? The story of Severe Acute Respiratory Syndrome (SARS) is given in standard textbooks [1]. The first cases appeared in Guandong, China in November 2002, but were not widely reported. Dr Carlo Urbani identified a case in Hanoi in February 2003 and urged the WHO into action, but soon succumbed to SARS himself. SARS coronavirus (SARS-CoV) was identified as the causative agent [2] and the palm civit the offending mammal vector that facilitated transfer from bats [1]. The cellular receptor was identified as angiotensin converting enzyme 2 [3]. Koch’s postulates were fulfilled when virus derived from cell culture produced pneumonia in macaques from whom SARS-CoV could be reisolated [4]. SARS-CoV was not highly contagious early in the disease course but, once the viral load peaked around day 10 of illness, the scene was set for transmission, especially when respiratory secretions were manipulated during clinical care. Standard precautions for control of infection, coupled with restrictions on international travel, were effective at terminating transmission and ending the pandemic, but left behind a case fatality rate of approximately 10% among the more than 8000 people affected [1]. Many treatments were tried in sick patients but without the controls necessary to determine if any intervention had beneficial or detrimental effects. Indeed, a systematic review,

Surviving another influenza threat.

Abstract: Another month brings another respiratory virus threatening a pandemic. This time, it is H7N9 infecting people in mainland China. According to a World Health Organization risk assessment dated 7 June 2013, 132 cases have occurred, with an excess in middle-aged men [1]. Contact with poultry was reported by most, with only limited evidence of human-to-human transmission in small clusters. The virus is multiple reassortant, with the haemagglutinin from an H7N3 strain, the neuraminidase from H7N9 and internal genes from at least two H9N2 strains [2]. Influenza viruses with H7 have caused human conjunctivitis previously, with one fatal case in a veterinarian [3], but it is unprecedented for N9 influenza viruses to infect humans. This is important, because the haemagglutinin and neuraminidase of an individual virus act in concert, so it is impossible to predict pathogenicity from the classification of a single protein [4]. Initial genetic studies predicted that the H7N9 viruses might have a good binding to the α2–6 receptors found in the human respiratory tract [2], but this was not confirmed in experiments using recombinant haemagglutinins [5]. Either we are being unlucky at the moment in being exposed to an unusual number of respiratory pathogens or our new technologies are allowing us to diagnose infections that would previously have remained hidden. There is evidence for both possibilities. Firstly, between 1968 and 2005, the population in China virtually doubled from 790 to 1300 million people, whereas the number of poultry went up more than 1000-fold from 12.3 to 13 000 million.[6] This abundance of chickens, coupled with close human contact required for their husbandry, could underlie a true increase in the number of transmissions of respiratory viruses. Secondly, the deaths of a few hundred people scattered throughout cities with generally poor life expectancy may not have attracted much public health attention a few decades ago. They certainly could not have been investigated in such detail as is now provided by modern molecular methods,