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Antiviral Research (v.78, #1)

Editorial Board (pp. ii).

Notes to Authors (pp. co3).

Highly pathogenic RNA viral infections: Challenges for antiviral research by Mike Bray (pp. 1-8).

A number of RNA viruses can cause severe disease when transmitted to humans from an animal reservoir. One of them, the recently emerged H5N1 subtype of influenza A virus, has caused several hundred cases of severe disease when transferred directly from domestic poultry. This or another avian subtype could potentially evolve to a form more transmissible by the respiratory route or reassort with a circulating strain to initiate a pandemic. Other zoonotic RNA viruses cause sporadic single cases or outbreaks of hemorrhagic fever or encephalitis that spread inefficiently from person-to-person, and thus remain confined to the geographic range of the maintenance host. RNA viral infections of farm animals, such as foot and mouth disease and classical swine fever, also pose a major threat to human well-being through economic loss and impaired nutrition. Only a few licensed antiviral drugs are available to prevent or treat these conditions. Medications that inhibit the replication of influenza virus might be used in an epidemic both to treat severe disease and to block the spread of infection. The guanosine analog ribavirin has been used to treat a few types of hemorrhagic fever, but there is no specific therapy for the others, or for any type of RNA viral encephalitis. The quest for new antivirals is being supported by government programs and new collaborative research networks. Major efforts will be required to identify active compounds, test their efficacy in laboratory animals, obtain approval for human use and develop rapid diagnostic methods that can identify patients early enough in the disease course for treatment to be of benefit.

Keywords: Viral hemorrhagic fever; Viral encephalitis; Arbovirus; Influenza; H5N1 influenza; Filovirus; Flavivirus; Yellow fever; Lassa fever; Lassa virus; Ebola hemorrhagic fever; Marburg hemorrhagic fever; Junin virus; Argentine hemorrhagic fever; Hantavirus; Hantavirus pulmonary syndrome; Crimean-Congo hemorrhagic fever; Arenavirus; Bunyavirus; Alphavirus; Japanese encephalitis; Zoonosis; Antiviral therapy; Antiviral drug; Emerging infectious diseases; Livestock diseases; Foot-and-mouth disease; Biodefense

Molecular strategies to inhibit the replication of RNA viruses by Pieter Leyssen; Erik De Clercq; Johan Neyts (pp. 9-25).

There are virtually no antiviral drugs available for the treatment of infections with RNA viruses. This is particularly worrisome since most of the highly pathogenic and emerging viruses are, and will likely continue to be, RNA viruses. These viruses can cause acute, severe illness, including severe respiratory disease, hemorrhagic fever and encephalitis, with a high case fatality rate. It is important to have potent and safe drugs at hand that can be used for the treatment or prophylaxis of such infections. Drugs approved for the treatment of RNA virus infections (other than HIV) are the influenza M2 channel inhibitors, amantadine and rimantadine; the influenza neuraminidase inhibitors, oseltamivir and zanamivir, and ribavirin for the treatment of infections with respiratory syncytial virus and hepatitis C virus. The molecular mechanism(s) by which ribavirin inhibits viral replication, such as depletion of intracellular GTP pools and induction of error catastrophe, may not readily allow the design of analogues that are more potent/selective than the parent drug. Highly pathogenic RNA viruses belong to a variety of virus families, each having a particular replication strategy, thus offering a wealth of potential targets to selectively inhibit viral replication. We here provide a non-exhaustive review of potential experimental strategies, using small molecules, to inhibit the replication of several RNA viruses. Other approaches, such as the use of interferon or other host-response modifiers, immune serum or neutralizing antibodies, are not addressed in this review.

Keywords: RNA viruses; Emerging viruses; Arenaviruses; Bunyaviruses; Flaviviruses; Filoviruses; Orthomyxoviruses; Ribavirin; Influenza; Avian influenza; Antiviral therapy

Oligonucleotide antiviral therapeutics: Antisense and RNA interference for highly pathogenic RNA viruses by Kevin B. Spurgers; C. Matthew Sharkey; Kelly L. Warfield; Sina Bavari (pp. 26-36).

RNA viruses are a significant source of morbidity and mortality in humans every year. Additionally, the potential use of these viruses in acts of bioterrorism poses a threat to national security. Given the paucity of vaccines or postexposure therapeutics for many highly pathogenic RNA viruses, novel treatments are badly needed. Sequence-based drug design, under development for almost 20 years, is proving effective in animal models and has moved into clinical trials. Important advances in the field include the characterization of RNA interference in mammalian cells and chemical modifications that can dramatically increase the in vivo stability of therapeutic oligonucleotides. Antisense strategies utilize single-stranded DNA oligonucleotides that inhibit protein production by mediating the catalytic degradation of target mRNA, or by binding to sites on mRNA essential for translation. Double-stranded RNA oligonucleotides, known as short-interfering RNAs (siRNAs), also mediate the catalytic degradation of complementary mRNAs. As RNA virus infection is predicated on the delivery, replication, and translation of viral RNA, these pathogens present an obvious target for the rapidly advancing field of sequence-specific therapeutics. Antisense oligonucleotides or siRNAs can be designed to target the viral RNA genome or viral transcripts. This article reviews current knowledge on therapeutic applications of antisense and RNA interference for highly pathogenic RNA viral infections.

Keywords: RNA virus; RNA interference; Antisense; siRNA; Phosphorodiamidate morpholino oligomer

The VIZIER project: Preparedness against pathogenic RNA viruses by B. Coutard; A.E. Gorbalenya; E.J. Snijder; A.M. Leontovich; A. Poupon; X. De Lamballerie; R. Charrel; E.A. Gould; S. Gunther; H. Norder; B. Klempa; H. Bourhy; J. Rohayem; E. L’hermite; P. Nordlund; D.I. Stuart; R.J. Owens; J.M. Grimes; P.A. Tucker; M. Bolognesi; A. Mattevi; M. Coll; T.A. Jones; J. Åqvist; T. Unge; R. Hilgenfeld; G. Bricogne; J. Neyts; P. La Colla; G. Puerstinger; J.P. Gonzalez; E. Leroy; C. Cambillau; J.L. Romette; B. Canard (pp. 37-46).

Life-threatening RNA viruses emerge regularly, and often in an unpredictable manner. Yet, the very few drugs available against known RNA viruses have sometimes required decades of research for development. Can we generate preparedness for outbreaks of the, as yet, unknown viruses? The VIZIER (VIral enZymes InvolvEd in Replication) (http://www.vizier-europe.org/) project has been set-up to develop the scientific foundations for countering this challenge to society. VIZIER studies the most conserved viral enzymes (that of the replication machinery, or replicases) that constitute attractive targets for drug-design. The aim of VIZIER is to determine as many replicase crystal structures as possible from a carefully selected list of viruses in order to comprehensively cover the diversity of the RNA virus universe, and generate critical knowledge that could be efficiently utilized to jump-start research on any emerging RNA virus. VIZIER is a multidisciplinary project involving (i) bioinformatics to define functional domains, (ii) viral genomics to increase the number of characterized viral genomes and prepare defined targets, (iii) proteomics to express, purify, and characterize targets, (iv) structural biology to solve their crystal structures, and (v) pre-lead discovery to propose active scaffolds of antiviral molecules.

Keywords: RNA virus; Genomics; Crystal structure; Replicase; Antivirals; Drug-design

International research networks in viral structural proteomics: Again, lessons from SARS by Bruno Canard; Jeremiah S. Joseph; Peter Kuhn (pp. 47-50).

Emerging and re-emerging pathogens and bioterror threats require an organized and coherent response from the worldwide research community to maximize available resources and competencies with the primary goals to understand the pathogen and enable intervention. In 2001, the Structural Proteomics In Europe (SPINE) project prototyped the pan-viral structural genomic approach, and the Severe Acute Respiratory Syndrome (SARS) outbreak in 2003 accelerated the concept of structural characterization of all proteins from a viral proteome and the interaction with their host partners. Following that approach, in 2004 the center for Functional and Structural Proteomics for SARS-CoV related proteins was initiated as part of the US NIH NIAID proteomics resource centers. Across worldwide efforts in Asia, Europe and America, the international research teams working on SARS-CoV have now determined experimental structural information for 45% of the SARS-CoV proteins and 53% of all its soluble proteins. This data is fully available to the scientific community and is providing an unprecedented level of insight to this class of RNA viruses. The efforts and results by the international scientific community to the SARS outbreak are serving as an example and roadmap of a rapid response using modern research methods.

Keywords: SARS-CoV; Infectious diseases; Structural genomics; FSPS; VIZIER

NIAID resources for developing new therapies for severe viral infections by Heather Greenstone; Beth Spinelli; Christopher Tseng; Susan Peacock; Katherine Taylor; Catherine Laughlin (pp. 51-59).

Severe viral infections, including hemorrhagic fever and encephalitis, occur throughout the world, but are most prevalent in developing areas that are most vulnerable to infectious diseases. Some of these can also infect related species as illustrated by the threatened extinction of gorillas by Ebola infection in west and central Africa. There are no safe and effective treatments available for these serious infections. In addition to the logistical difficulties inherent in developing a drug for infections that are sporadic and occur mainly in the third world, there is the overwhelming barrier of no hope for return on investment to encourage the pharmaceutical industry to address these unmet medical needs. Therefore, the National Institute of Allergy and infectious Disease (NIAID) has developed and supported a variety of programs and resources to provide assistance and lower the barrier for those who undertake these difficult challenges. The primary programs relevant to the development of therapies for severe viral infections are described and three case studies illustrate how they have been used. In addition, contact information for accessing these resources is supplied.

Keywords: Adenoviruses; Anti-inflammatory; Antiviral testing program; Avian H5N1; BEIR; Biodefense and emerging infections repository; BK virus; BLA; BSL-4 containment; Cationic lipid–DNA complexes (CLDC); Chemical synthesis; Clinical evaluations; Cloned genes; Cowpox virus; Cytomegalovirus; Dengue; Determination of exceptional circumstances (DEC); Epstein-Barr virus; Filoviruses; Formulation; Hamster-scrapie; Hepatitis B virus; Hepatitis C virus; Herpes simplex type 1 and type 2; Highly pathogenic RNA viruses; HIV; Human herpes virus 6; Human herpes virus 8; Immunomodulatory; In vivo; testing submission form; IND; Influenza type A; Intellectual property option (IP option); Intellectual property; Junin; Juvaris BioTherapeutics; Lassa fever; Manufacturing; Measles; Medicinal chemistry; Monoclonal antibodies; NDA; NIAID Category A, B and C; NIAID; Nucleic acids; Orthopoxviruses; Papillomaviruses; Parainfluenza; Patent protection; Pharmacodynamic; Pharmacokinetic; Phase I clinical trials; Pichinde; Radiolabeled compounds; Recombinant proteins; Respiratory syncytial virus; Rhinoviruses; Rift valley fever; Screening agreement; Services for the preclinical development of therapeutic agents; Severe acute respiratory syndrome (SARS)-associated coronavirus; Synthesis/resynthesis; Synthetic peptides; Tacaribe; Vaccinia virus; Varicella-Zoster virus; Venezuelan equine encephalitis; West nile; Western equine encephalitis viruses; Yellow fever

FDA perspective on antivirals against biothreats: Communicate early and often by Rosemary Roberts; Barbara Styrt; Susan McCune (pp. 60-63).

Development of antiviral products for certain highly pathogenic viruses with limited available treatments, such as viruses that may have biothreat potential, is critically important and challenging. The mission of the FDA is to protect the public health by assuring the safety, efficacy and quality of such products. Human clinical trials are critically important whenever relevant naturally occurring diseases can appropriately be studied. In selected situations when clinical studies are not ethical and field efficacy studies are not feasible, the Animal Rule (67 FR 37988, 2002) introduces the possibility of drug/biologic approval/licensure based on efficacy studies in animals, and appropriate human safety and pharmacokinetic information. This approach necessitates the development of well-delineated animal models predictive of human disease and treatment responses, and plans for adding human information if suitable circumstances arise. Efficient development of therapeutics against these agents requires collaborative efforts among industry, academia and federal agencies.

Keywords: Food and Drug Administration (FDA); Highly pathogenic viruses; Antiviral products; Drug development; Clinical trials; Animal Rule; Biothreats; Drugs; Therapeutic biologics

The Southeast Asian Influenza Clinical Research Network: Development and challenges for a new multilateral research endeavor by Elizabeth S. Higgs; Frederick G. Hayden; Tawee Chotpitayasunondh; Jimmy Whitworth; Jeremy Farrar (pp. 64-68).

The Southeast Asia Influenza Clinical Research Network (SEA ICRN) (www.seaclinicalresearch.org) is a recently developed multilateral, collaborative partnership that aims to advance scientific knowledge and management of human influenza through integrated clinical investigation. The partnership of hospitals and institutions in Indonesia, Thailand, United Kingdom, United States, and Viet Nam was established in late 2005 after agreement on the general principles and mission of the initiative and after securing initial financial support. The establishment of the SEA ICRN was both a response to the re-emergence of the highly pathogenic avian influenza A(H5N1) virus in Southeast Asia in late 2003 and an acknowledgment that clinical trials on emerging infectious diseases require prepared and coordinated research capacity. The objectives of the Network also include building sustainable research capacity in the region, compliance with international standards, and prompt dissemination of information and sharing of samples. The scope of research includes diagnosis, pathogenesis, treatment and prevention of human influenza due to seasonal or novel viruses. The Network has overcome numerous logistical and scientific challenges but has now successfully initiated several clinical trials. The establishment of a clinical research network is a vital part of preparedness and an important element during an initial response phase to a pandemic.

Keywords: Developing networks; Emerging infectious diseases; Clinical research; Pandemic preparedness; Avian influenza; H5N1 influenza; Southeast Asia

Animal models of highly pathogenic RNA viral infections: Encephalitis viruses by Michael R. Holbrook; Brian B. Gowen (pp. 69-78).

The highly pathogenic RNA viruses that cause encephalitis include a significant number of emerging or re-emerging viruses that are also considered potential bioweapons. Many of these viruses, including members of the family Flaviviridae, the genus Alphavirus in the family Togaviridae, and the genus Henipavirus in the family Paramyxoviridae, circulate widely in their endemic areas, where they are transmitted by mosquitoes or ticks. They use a variety of vertebrate hosts, ranging from birds to bats, in their natural life cycle. As was discovered in the United States, the introduction of a mosquito-borne encephalitis virus such as West Nile virus can cause significant health and societal concerns. There are no effective therapeutics for treating diseases caused by any of these viruses and there is limited, if any, vaccine availability for most. In this review we provide a brief summary of the current status of animal models used to study highly pathogenic encephalitic RNA viruses for the development of antiviral therapeutics and vaccines.

Keywords: Flavivirus; Alphavirus; Henipavirus; Encephalitis; Small animal model

Animal models of highly pathogenic RNA viral infections: Hemorrhagic fever viruses by Brian B. Gowen; Michael R. Holbrook (pp. 79-90).

A diverse group of highly pathogenic RNA viruses cause a severe multisystemic illness in humans commonly referred to as viral hemorrhagic fever (VHF). Although they can vary widely in clinical presentation, all VHFs share certain features that include intense fever, malaise, bleeding and shock. Effective antiviral therapies for most of the VHFs are lacking. Complicating development of intervention strategies is the relative infrequency and unpredictability of VHF outbreaks making human clinical trials extremely challenging or unfeasible. Therefore, animal models that can recapitulate human disease are essential to the development of effective antivirals and vaccines. In general, a good animal model of VHF will demonstrate systemic dispersion of the virus through infection of mononuclear phagocytes and dendritic cells, which induces the release of inflammatory mediators that increase vascular permeability and facilitate coagulation. The culmination of this process leads to significant loss of plasma volume and terminal hypovolemic shock. Although it is clear that nonhuman primate models are the most faithful to human disease, the more accessible and less costly rodent models, including those based on infection with related surrogate viruses, can reproduce certain components of VHF and can serve as suitable preclinical models for initial development of effective countermeasures. Such models are sufficient for testing of drugs that directly block viral replication, but may be inadequate for evaluating therapies that depend for their success on the activation or inhibition of host responses.

Keywords: Animal model; RNA virus; Viral hemorrhagic fever; Flavivirus; Bunyavirus; Arenavirus; Lassa fever; Junin virus; Argentine hemorrhagic fever; Filovirus; Ebola virus; Marburg virus; Yellow fever; Dengue hemorrhagic fever; Dengue virus; Rift Valley fever; Crimean-Congo hemorrhagic fever; Hantavirus; Hantaviral pulmonary syndrome; Hemorrhagic fever with renal syndrome

Current and future antiviral therapy of severe seasonal and avian influenza by John Beigel; Mike Bray (pp. 91-102).

The currently circulating H3N2 and H1N1 subtypes of influenza A virus cause a transient, febrile upper respiratory illness in most adults and children (“seasonal influenza”), but infants, the elderly, immunodeficient and chronically ill persons may develop life-threatening primary viral pneumonia or complications such as bacterial pneumonia. By contrast, avian influenza viruses such as the H5N1 virus that recently emerged in Southeast Asia can cause severe disease when transferred from domestic poultry to previously healthy people (“avian influenza”). Most H5N1 patients present with fever, cough and shortness of breath that progress rapidly to adult respiratory distress syndrome. In seasonal influenza, viral replication remains confined to the respiratory tract, but limited studies indicate that H5N1 infections are characterized by systemic viral dissemination, high cytokine levels and multiorgan failure. Gastrointestinal infection and encephalitis also occur. The licensed anti-influenza drugs (the M2 ion channel blockers, amantadine and rimantadine, and the neuraminidase inhibitors, oseltamivir and zanamivir) are beneficial for uncomplicated seasonal influenza, but appropriate dosing regimens for severe seasonal or H5N1 viral infections have not been defined. Treatment options may be limited by the rapid emergence of drug-resistant viruses. Ribavirin has also been used to a limited extent to treat influenza. This article reviews licensed drugs and treatments under development, including high-dose oseltamivir; parenterally administered neuraminidase inhibitors, peramivir and zanamivir; dimeric forms of zanamivir; the RNA polymerase inhibitor T-705; a ribavirin prodrug, viramidine; polyvalent and monoclonal antibodies; and combination therapies.

Keywords: Influenza; Influenza virus; Avian influenza; H5N1 influenza virus; Adamantane; Neuraminidase; Peramivir; Oseltamivir; Zanamivir; Antiviral therapy

New opportunities for field research on the pathogenesis and treatment of Lassa fever by Sheik Humarr Khan; Augustine Goba; May Chu; Cathy Roth; Tim Healing; Arthur Marx; Joseph Fair; Mary C. Guttieri; Philip Ferro; Tiffany Imes; Corina Monagin; Robert F. Garry; Daniel G. Bausch (pp. 103-115).

Unlike many viral hemorrhagic fevers (VHFs), Lassa fever (LF) is not a rare disease that emerges only as sporadic cases or in outbreak form. Although surveillance is inadequate to determine the true incidence, up to 300,000 infections and 5000 deaths from LF are estimated to occur yearly. The highest incidence is in the “Mano River Union (MRU) countries” of Sierra Leone, Liberia, and Guinea. Although civil unrest in this region over the past two decades has impeded capacity building and research, new-found peace in recent years presents new opportunities. In 2004, the Mano River Union Lassa Fever Network (MRU LFN) was established to assist MRU countries in the development of national and regional surveillance, diagnosis, treatment, control, and prevention of LF. Here, we review the present literature on treatment and pathogenesis of LF and outline priorities for future research in the field made possible by the improved research capacity of the MRU LFN.

Keywords: Lassa virus; Lassa fever; Arenavirus; Viral hemorrhagic fever; West Africa; Antiviral therapy; Ribavirin; Pathogenesis

Treatment of yellow fever by Thomas P. Monath (pp. 116-124).

Yellow fever (YF) is a life-threatening mosquito-borne flaviviral hemorrhagic fever (VHF) characterized by severe hepatitis, renal failure, hemorrhage, and rapid terminal events with shock and multi-organ failure. A live, attenuated vaccine (YF 17D), in wide use for over 60 years, causes a disease identical to wild-type virus at an incidence of 2.5×10⁻⁶. Our current understanding of the pathogenesis and treatment of YF (described in this brief review) is derived from studies of animal models (macaques, hamsters) that reproduce the features of human YF and from descriptive studies of human cases of naturally acquired and vaccine-associated VHF. The least understood, but potentially most important terminal events appear to be due to ‘cytokine storm’ and represent a potential target for therapeutic interventions. Areas for future study include dissection of cytokine-mediated events in animal models, the pathogenic role of the profound neutrophilia that occurs pre-terminally, the (pathological) role of adaptive immune clearance in pathogenesis, and treatments directed at cytokine storm. Antibody, interferon-α, polyICLC and other immune modulators are highly effective when administered before or within a narrow time window after infection, but are ineffective when given after the infection is established. A few antivirals have been evaluated (ribavirin, tiazofurin, carboxamide, pyrazoline compounds). Ribavirin has been used successfully to treat hamsters when the drug is given at high doses up to 2 days after virus infection (shortly before liver infection), but has not shown promise in nonhuman primate models. Future work should focus on evaluating higher doses of ribavirin alone or in combinations with potentially synergistic drugs, including interferons. Also specific inhibitors against other flaviviruses such as dengue virus should be investigated for potential pan–flavivirus activity since recent studies have shown that specific targets such as the flavivirus proteases and helicases are very similar in structure.

Keywords: Yellow fever; Antivirals; Interferon; Pathogenesis

Treatment of Crimean-Congo hemorrhagic fever by Onder Ergonul (pp. 125-131).

Crimean-Congo hemorrhagic fever (CCHF) has the most extensive geographic range of the medically significant tick-borne viruses, occurring from western China across southern Asia to eastern Europe and South Africa. The causative agent is a negative-sense, single-stranded RNA virus in the genus Nairovirus, family Bunyaviridae. In published reports, the case fatality rate has generally ranged from 10% to 50%. Sporadic cases and outbreaks of the disease have increased during the past decade across the endemic region. CCHF was first diagnosed in Turkey in 2002, but since then more than 1100 cases have been confirmed by IgM serology or RT-PCR, with a fatality rate of just over 5%. Simple methods are available for the in vitro evaluation of antiviral drugs, but because CCHF virus does not cause disease in its reservoir species or in laboratory animals other than suckling mice, methods are lacking for in vivo efficacy testing. Intravenous or oral ribavirin has been used in several countries to treat the disease for more than 20 years. Evidence of its efficacy is limited to observational studies, and placebo-controlled trials may be impossible to perform for ethical reasons. However, careful analysis of properly stratified observational studies can be used to assess the effects of treatment. This article reviews current approaches to the treatment of CCHF, focusing on the use of ribavirin and hematological support, and discusses prospects for future research.

Keywords: Crimean-Congo hemorrhagic fever; Ribavirin; Bunyavirus; Emerging infections; Viral hemorrhagic fever; Arbovirus; Antiviral therapy; Biodefense

Treatment of Argentine hemorrhagic fever by Delia A. Enria; Ana M. Briggiler; Zaida Sánchez (pp. 132-139).

Argentine hemorrhagic fever (AHF) is a rodent-borne illness caused by the arenavirus Junin that is endemic to the humid pampas of Argentina. AHF has had significant morbidity since its emergence in the 1950s, with a case-fatality rate of the illness without treatment between 15% and 30%. The use of a live attenuated vaccine has markedly reduced the incidence of AHF. Present specific therapy involves the transfusion of immune plasma in defined doses of neutralizing antibodies during the prodromal phase of illness. However, alternative forms of treatment are called for due to current difficulties in early detection of AHF, related to its decrease in incidence, troubles in maintaining adequate stocks of immune plasma, and the absence of effective therapies for severely ill patients that progress to a neurologic–hemorrhagic phase. Ribavirin might be a substitute for immune plasma, provided that the supply is guaranteed. Immune immunoglobulin or monoclonal antibodies should also be considered. New therapeutic options such as those being developed for systemic inflammatory syndromes should also be valuated in severe forms of AHF.

Keywords: Argentine hemorrhagic fever; Viral hemorrhagic fever; Arenavirus; Junin virus

Does antiviral therapy have a role in the control of Japanese encephalitis? by E.A. Gould; T. Solomon; J.S. Mackenzie (pp. 140-149).

Approximately 2 billion people live in countries where Japanese encephalitis (JE) presents a significant risk to humans and animals, particularly in China and India, with at least 700 million potentially susceptible children. The combined effects of climate change, altered bird migratory patterns, increasing movement of humans, animals and goods, increasing deforestation and development of irrigation projects will inevitably lead to further geographic dispersal of the virus and an enhanced threat. Although most human infections are mild or asymptomatic, some 50% of patients who develop encephalitis suffer permanent neurologic defects, and 25% die. Vaccines have reduced the incidence of JE in some countries. No specific antiviral therapy is currently available. Interferon alpha-2a was tested in a double-blind placebo-controlled trial on children with Japanese encephalitis, but with negative results. There is thus a real need for antivirals that can reduce the toll of death and neurological sequelae resulting from infection with JE virus. Here we briefly review the epidemiological problems presented by this virus, the present state of drug development and the contributory role that antiviral therapy might play in developing future control strategies for JE.

Keywords: Antivirals; Antiviral therapy; Japanese encephalitis; Japanese encephalitis virus; Control strategies

Treatment of Marburg and Ebola hemorrhagic fevers: A strategy for testing new drugs and vaccines under outbreak conditions by Daniel G. Bausch; A.G. Sprecher; Benjamin Jeffs; Paul Boumandouki (pp. 150-161).

The filoviruses, Marburg and Ebola, have the dubious distinction of being associated with some of the highest case-fatality rates of any known infectious disease—approaching 90% in many outbreaks. In recent years, laboratory research on the filoviruses has produced treatments and vaccines that are effective in laboratory animals and that could potentially drastically reduce case-fatality rates and curtail outbreaks in humans. However, there are significant challenges in clinical testing of these products and eventual delivery to populations in need. Most cases of filovirus infection are recognized only in the setting of large outbreaks, often in the most remote and resource-poor areas of sub-Saharan Africa, with little infrastructure and few personnel experienced in clinical research. Significant political, legal, and socio-cultural barriers also exist. Here, we review the present research priorities and environment for field study of the filovirus hemorrhagic fevers and outline a strategy for future prospective clinical research on treatment and vaccine prevention.

Keywords: Ebola virus; Ebolavirus; Marburg virus; Marburgvirus; Filovirus; Viral hemorrhagic fever; Clinical research; Treatment; Vaccine; Emerging infectious disease; Biodefense

Treatment of hantavirus pulmonary syndrome by Colleen B. Jonsson; Jay Hooper; Gregory Mertz (pp. 162-169).

Viruses in the genus Hantavirus can cause one of two serious illnesses when transmitted from rodents to humans: hemorrhagic fever with renal syndrome (HFRS) or hantavirus pulmonary syndrome (HPS). Of the two diseases, HPS is more severe with an approximate 40% mortality across the Americas. The high rate of mortality could be reduced if effective therapeutics could be discovered for treatment of this illness. Herein we review approaches being explored for the discovery of therapeutics for HPS and how they could be employed in treatment and prevention of disease.

Keywords: Hantavirus; HPS; HFRS; Hantavirus pulmonary syndrome; Bunyavirus; Antiviral therapy; Ribavirin

Potential of antiviral therapy and prophylaxis for controlling RNA viral infections of livestock by Nesya Goris; Frank Vandenbussche; Kris De Clercq (pp. 170-178).

With intensification of trade, livestock are increasingly exposed to severe animal diseases caused by a range of RNA viruses. Recent prime examples include outbreaks of foot-and-mouth disease (FMD), peste des petits ruminants, Rift Valley fever and bluetongue. To minimise their impact, controlling the spread of virus is of utmost importance. Good quality, reliable vaccines exist for some, although not all, of these diseases, but suffer from a set of drawbacks, not the least of which being the time needed to trigger the immune response (i.e. “immunity-gap”). Effective, rapid control tools are, therefore, urgently needed and antiviral compounds could serve this purpose. Although limited in vitro and in vivo research has been performed, encouraging results for FMD suggest that livestock could be protected against infection within 24h following antiviral treatment and up to 12h post-infection. Such prophylactic/therapeutic antiviral drugs could complement emergency vaccination in a previously disease-free setting or be applied to treat valuable zoological collections and breeding stocks in endemic and previously disease-free regions alike. This paper will primarily focus on the effects of FMD on livestock and other sectors, and on appropriate control tools. The outlined principles can be extrapolated to other RNA viral diseases.

Keywords: RNA virus; Control; Stamping out; Vaccination; Antiviral; Foot-and-mouth disease; Rift Valley fever; Classical swine fever; Avian influenza; Newcastle disease; Peste des petits ruminants; Rinderpest; Swine vesicular disease; African horse sickness; Bluetongue; Vesicular stomatitis; Livestock

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Antiviral Research (v.78, #1)