Infectious Disorders - Drug Targets (Formerly Current Drug Targets - Infectious Disorders) - Volume 11, Issue 3, 2011

Human encephalitis is a complex neurological syndrome constituting a challenging public health problem. This severe disease, defined as the combination of an inflammation of the brain parenchyma and neurological dysfunction, is associated with high rates of mortality and morbidity. Several causes of encephalitis have been identified, but infectious agents remain the most common. These agents include various microorganisms, with viruses the most frequently implicated. Over the last two decades, several studies have provided insight into the overall clinical, epidemiological and etiological picture of viral encephalitis, but our knowledge remains far from complete. The incidence of the main viral etiological agents of encephalitis, including herpesviruses (herpes simplex viruses and varicella zoster virus in particular), enteroviruses, several arboviruses and nonarthropod-borne viral zoonotic pathogens, such as the rabies and nipah viruses, has been determined. However, the inventory of viruses responsible for encephalitis is not exhaustive, with gaps depending on the strategy or standardized procedures used for virus identification and the tools available for diagnosis. A high proportion of acute encephatitis cases remain of unknown etiology and it seems likely that other viruses are responsible for these cases. Moreover, this inventory is not fixed and it should be updated based on geographic, socioeconomic, public health or even climatic considerations (particularly for arboviruses). This need for change is exemplified by the introduction of an unprecedented number of encephalitic viruses, which have emerged or spread worldwide over the last decade, particularly in the Southeast Asian and Western Pacific regions. The treatment strategies for patients suffering from viral encephalitis remain extremely limited. Indeed, other than for herpesviruses (more precisely, herpes simplex viruses), no drug has yet been clearly demonstrated to be efficient, with validated activity against a broad range of the viral agents of encephalitis identified to date. The management of patients is based principally on symptomatic treatment. There is therefore a great need for research in this field, and current efforts are focused on the development of novel antiviral drugs, with the prospect of rapidly delivering effective treatments for this devastating syndrome. In this context, the special topic of Infectious Disorders - Drug Targets in this issue is viral encephalitis, and attempts have been made to cover very different and complementary aspects of the field. An up-to-date overview of several diagnosis tools for virus identification, focusing in particular on the most recent advances, presented by K. Mutton and M. Guiver, in “Laboratory Techniques for Human Viral Encephalitis Diagnosis”. A selection of five major viruses causing encephalitis in humans is then presented, each starting from the specific biological background of the virus and moving on to the various molecular targets and antiviral drugs that have been tested to date, are available or in development. We begin with herpes simplex viruses, presented by F. Rozenberg, C. Deback and H. Agut in their review “Herpes simplex encephalitis: from virus to therapy”. These viruses are among the most common causes of viral encephalitis in humans, but they also provide an example of the successful development and use of an effective antiviral drug, in the form of acyclovir. The next two viruses presented are the rabies and Japanese encephalitis viruses. Rabies is a deadly reemerging virus and Japanese encephalitis virus is an emerging agent. Effective prophylactic vaccination exists for both these viruses, but they nonetheless continue to cause high rates of death, particularly in developing countries, and no active antiviral drugs are available. The state-of-the art concerning potential new strategies for the prevention and cure of infections caused by rabies virus is reviewed by L. Dacheux, O. Delmas and H. Bourhy in their article entitled Human “Rabies Encephalitis Prevention and Treatment: Progress Since Pasteur's Discovery”. Dutta K., A. Nazmi and A. Basu present a complete review of recent advances in our knowledge of Japanese encephalitis virus and antiviral drug development in “Chemotherapy in Japanese encephalitis: are we there yet?”. Finally, two examples of challenging antiviral drug developments for two other major emerging viruses responsible for encephalitis are presente. The first of these two examples is henipaviruses, reviewed by F. Vigant and B. Lee in their article “Hendra and nipah infection: pathology, models and potential therapies”. The final example is provided by enteroviruses, presented by T.C. Chen and S.R. Shih, in their review entitled “Drug Discovery in Enteroviral Infections”. I am convinced that the high quality and relevance of each of these state-of-the-art reviews will ensure that they of considerable interest to the scientific community working in the field of viral encephalitis in humans, and also to the larger community of scientists involved in the challenging enterprise of developing innovative new antiviral drugs....

Encephalitis is an inflammatory process involving the parenchyma of the brain. It typically presents as a clinical syndrome characterised by fever, headache and altered conscious level, often with focal neurological deficits and fits. The clinical presentation overlaps with other diseases of the central nervous system including viral and bacterial meningitis, and brain abscess. The causes of encephalitis are legion, and include principally viral but also bacterial, parasitic and fungal pathogens. Noninfectious aetiologies, especially autoimmune conditions such as potassium channel voltage gated antibodies and anti-NDMA receptor antibodies, are increasingly recognised. Diagnosis comes from clinical examination, neuroimaging and laboratory testing. With such a wide range of potential pathogens a syndromic approach to diagnosis is preferred, testing for a range of organisms. Traditional techniques such as cell culture and direct virus antigen detection have little or no role nowadays. Laboratory diagnosis of viral encephalitis is ideally based on examination of cerebrospinal fluid (CSF) for cells, protein and glucose, followed by nucleic acid amplification tests (NAAT) such as polymerase chain reaction (PCR) for a range of viral targets. Samples other than CSF sometimes give a definitive or probable aetiological diagnosis; examples include skin biopsy in rabies, and serum NAAT and antibody tests for some arboviruses and enteroviruses. Newer approaches to amplification and to multitarget detection are becoming increasingly important. Detection of intrathecal antibody production against specific viruses retains a place in diagnosis where NAAT is negative. Some of the laboratory techniques available will be discussed in this article.

Herpes simplex virus (HSV) is the cause of herpes simplex encephalitis (HSE), a devastating human disease which occurs in 2-4 cases per million/year. HSE results either from a primary infection or virus reactivation, in accordance with the common pattern of HSV infection which is a chronic lifelong process. However its pathophysiology remains largely unknown and its poor prognosis is in contrast with the usually good tolerance of most clinical herpetic manifestations. HSE is due to HSV type 1 (HSV-1) in most cases but HSV type 2 (HSV-2) may be also implicated, especially in infants in the context of neonatal herpes. Polymerase chain reaction detection of HSV DNA in cerebrospinal fluid is the diagnosis of choice for HSE. Acyclovir, a nucleoside analogue which inhibits viral DNA polymerase activity, is the reference treatment of HSE while foscarnet constitutes an alternative therapy and the efficacy of cidofovir is currently uncertain in that context. The emergence of HSV resistance to acyclovir, a phenomenon which is mainly observed among immunocompromised patients, is a current concern although no case of HSE due to an acyclovir-resistant HSV strain has been reported to date. Nevertheless the identification and development of novel therapeutic strategies against HSV appears to be a non dispensable objective for future research in virology.

Rabies remains one of the most ancient and deadly of human infectious diseases. This viral zoonosis is transmitted principally by the saliva of infected dogs, inducing a form of encephalomyelitis that is almost invariably fatal. Since the first implementation, by Louis Pasteur in 1885, of an efficient preventive post-exposure treatment, more effective protocols and safer products have been developed, providing almost 100% protection if administered early enough. However, this disease still represents a major, but neglected public health problem, with an estimated 55,000 human deaths due to rabies reported each year, mostly in Africa and Asia. Once the first clinical signs appear, there is no effective treatment. A ray of hope emerged in 2004, with the report of a patient recovering from rabies after aggressive, innovative treatment. However, this case was not clearly reproduced and the identification of targets for antiviral treatment in cases of rabies infection remains a major challenge. In this context, this review presents the state-of-the art in the prevention and curative treatment of human rabies. We begin by describing the viral etiological agent and the disease it causes, to provide an essential background to rabies. An overview of the post-exposure prophylaxis of rabies in humans is then given, from its initial implementation to possible future developments. Finally, an analysis of the various antiviral compounds tested in rabies in vitro, in animal models or in humans is presented, focusing in particular on potential new strategies.

Chemotherapy in Japanese encephalitis (JE) is at present entirely supportive and not targeted at the virus. There are no available drugs to effectively counter the viral infection, thereby making the fight against JE a daunting task. With approximately 50,000 reported cases per year, nearly 10,000 deaths and 3 billion people living in endemic regions, it is imperative that the hunt for an effective drug be expedited. Prophylactic measures are effective against JE, but the problem plaguing all is the underdevelopment and inefficiency of medical services in developing countries. Combined to that are difficulties to earn a living and illiteracy, that leaves significant proportions of the population in these countries uninformed about the magnitude of the threat and uninterested in the potential benefits of prophylactic strategies. Thus, for such countries coming under the JE endemic region, the need for developing therapeutic strategies that are cheap, easily available and with no or tolerable side effects, becomes significant. With rapid globalization and a gradual shift in global climate, JEV, like many other flaviviruses, may emerge in newer areas. This review is an effort to briefly outline the chemotherapeutic approaches adopted over the years in developing effective therapeutic countermeasures against this deadly disease and highlights the promising avenues that need to be treaded in order to win the war against JEV.

The Paramyxoviridae family comprises of several genera that contain emerging or re-emerging threats for human and animal health with no real specific effective treatment available. Hendra and Nipah virus are members of a newly identified genus of emerging paramyxoviruses, Henipavirus. Since their discovery in the 1990s, henipaviruses outbreaks have been associated with high economic and public health threat potential. When compared to other paramyxoviruses, henipaviruses appear to have unique characteristics. Henipaviruses are zoonotic paramyxoviruses with a broader tropism than most other paramyxoviruses, and can cause severe acute encephalitis with unique features among viral encephalitides. There are currently no approved effective prophylactic or therapeutic treatments for henipavirus infections. Although ribavirin was empirically used and seemed beneficial during the biggest outbreak caused by one of these viruses, the Nipah virus, its efficacy is disputed in light of its lack of efficacy in several animal models of henipavirus infection. Nevertheless, because of its highly pathogenic nature, much effort has been spent in developing anti-henipavirus therapeutics. In this review we describe the unique features of henipavirus infections and the different strategies and animal models that have been developed so far in order to identify and test potential drugs to prevent or treat henipavirus infections. Some of these components have the potential to be broad-spectrum antivirals as they target effectors of viral pathogenecity common to other viruses. We will focus on small molecules or biologics, rather than vaccine strategies, that have been developed as anti-henipaviral therapeutics.

Enteroviruses (EVs) are common and significant human pathogens in Asia. EV infections can cause a wide spectrum of acute diseases, including CNS complications. These EV infection-related CNS syndromes include acute flaccid paralysis, aseptic meningitis, encephalitis, and even death. Currently, there is no vaccine available for most EVs except for poliovirus; furthermore, there is a lack of clinical antiviral drugs for treating EV-related infections. These shortages reveal the need to develop potent compounds for treating enteroviral infections. This study summarizes the development of drugs for EV-related infections based on molecular targets blocking various steps in the viral replication cycle.