Current Molecular Medicine - Volume 5, Issue 8, 2005

Arenaviruses merit significant attention both as tractable model systems to study acute and persistent viral infections, and as clinically important human pathogens. Evidence indicates that LCMV remains present in the USA and Europe and capable of causing significant morbidity in infected individuals, likely being a neglected human pathogen. Moreover, new arenaviruses are being discovered in the Americas on the average of one every three years, with some of them causing severe hemorrhagic fever. In addition, weaponized forms of these viruses pose a real threat as agents of bioterrorism. Therefore, it is important to develop effective vaccines and better antiviral drugs to combat the dual threats of naturally occurring and intentionally introduced Arenavirus infections. The development of arenavirus reverse genetic systems is allowing investigators to conduct a detailed molecular characterization of the viral cis-acting signals and trans-acting factors that control each of the steps of the Arenavirus life cycle, including RNA synthesis, packaging and budding. We will discuss how this new knowledge is facilitating the establishment of novel assays to identify and characterize compounds capable of interfering with specific steps of the virus life cycle. Likewise, the ability to generate predetermined specific mutations within the arenavirus genome, and analyze their phenotypic expression, would significantly contribute to the elucidation of arenavirus-host interactions, including the bases of their ability to persist, as well as to cause severe HF (hemorrhagic fever) disease in humans. These approaches could also lead to the development of novel potent and safe Arenavirus vaccines.

Crimean-Congo hemorrhagic fever virus (CCHFV) is an important human pathogen, which is the cause of a tick-borne illness occurring in many areas of Africa, Asia, and Europe. CCHF is characterized by a sudden onset of high fever, chills, and severe headache. Other symptoms can include gastrointestinal disorders, such as nausea, vomiting, and diarrhea. In severe cases, hemorrhagic manifestations can occur and often present as large areas of ecchymosis, rather than frank bleeding. Exposure to ticks, particularly those in the genus Hyalomma, or direct contact with virus-infected animals or people are considered the major risk factors. Studies on CCHFV are impeded by the biocontainment needed for their manipulation. However, the increasing worldwide medical awareness, the enormous interest of the media in hemorrhagic fever diseases, and their potential to be used as a bioweapon, have greatly spurred on research on this important virus, as evidenced by many new developments including the development of a reverse genetics system which should greatly enhance future research with this virus.

Ebola and Marburg viruses, family Filoviridae, are among the best known examples of emerging and re-emerging pathogens. Although outbreaks have been sporadic and geographically restricted to areas of Central Africa, the hemorrhagic fevers caused by these viruses are remarkably severe and are associated with high case fatality rates often exceeding 80 percent. In addition to humans, these viruses have decimated populations of wild apes in Central Africa. Currently, there are no vaccines or effective therapies available for human use. Progress in understanding the geneses of the pathophysiological changes that make filoviral infections of humans so destructive has been slow, primarily because these viruses require special containment for safe research. However, an increasing understanding of the molecular mechanisms of filoviral pathogenesis, facilitated by the development of new tools to elucidate critical regulatory elements in the viral life cycle, is providing new targets that can be exploited for therapeutic interventions. In addition, substantial progress has been made in developing recombinant vaccines against these viruses.

Hantaviruses are tri-segmented negative sense single stranded RNA viruses that belong to the family Bunyaviridae. In nature, hantaviruses are exclusively maintained in the populations of their specific rodent hosts. In their natural host species, hantaviruses usually develop a persistent infection with prolonged virus shedding in excreta. Humans become infected by inhaling virus contaminated aerosol. Unlike asymptomatic infection in rodents, hantaviruses cause two acute febrile diseases in humans: hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). The mortality rate varies from 0.1% to 40% depending on the virus involved. Hantaviruses are distributed world wide, with over 150,000 HFRS and HPS cases being registered annually. In this review we summarize current knowledge on hantavirus molecular biology, epidemiology, genetic diversity and co-evolution with rodent hosts. In addition, special attention was given in this review to describing clinical manifestation of HFRS and HPS, and advances in our current understanding of the host immune response, treatment, and prevention.

Influenza is an example of a disease for which the viral pathogen has emerged into the human population many times over past centuries, sometimes with devastating consequences [1]. Historical records provide vivid descriptions of past influenza outbreaks, and the viruses that caused the pandemics of the last century remain subjects of great interest. It is almost certain that a new pandemic, caused by the zoonotic transmission of a new influenza virus into humans, will occur. The recent outbreaks of the highly pathogenic H5 and H7 subtype viruses in poultry and their limited transmission into humans, as well as transmission of H9 subtype viruses, have raised concerns that conditions are developing for the generation of a new pandemic virus. In this paper, we review past pandemics, viral determinants of cross-species transmission of viruses, molecular factors that contribute to disease, and preventative measures to reduce the impact of a future pandemic.

Within the past decade a number of new zoonotic paramyxoviruses emerged from flying foxes to cause serious disease outbreaks in man and livestock. Hendra virus was the cause of fatal infections of horses and man in Australia in 1994, 1999 and 2004. Nipah virus caused encephalitis in humans both in Malaysia in 1998/99, following silent spread of the virus in the pig population, and in Bangladesh from 2001 to 2004 probably as a result of direct bat to human transmission and spread within the human population. Hendra and Nipah viruses are highly pathogenic in humans with case fatality rates of 40% to 70%. Their genetic constitution, virulence and wide host range make them unique paramyxoviruses and they have been given Biosecurity Level 4 status in a new genus Henipavirus within the family Paramyxoviridae. Recent studies on the virulence, host range and cell tropisms of henipaviruses provide insights into the unique biological properties of these emerging human pathogens and suggest approaches for vaccine development and therapeutic countermeasures.

Variola, the agent of smallpox, is a bioterrorist threat, as is monkeypox virus, which also occurs naturally in Africa. Development of countermeasures, in the form of improved vaccines, antiviral drugs, and other therapeutic strategies are a high priority. Recent advances in molecular biology and in animal model development have provided fresh insight into the virulence determinants for smallpox and the pathophysiology of disease. The complex replication cycle for orthopoxviruses, and the pivotal role for viralspecific immunomodulatory proteins which contribute to escape from immunologic surveillance, provide many unique targets for therapeutic intervention. The "toxemia" of smallpox has been elucidated in part by variola-infected primate studies which revealed the central role of apoptosis and the evolution of a cytokine storm leading to hemorrhagic diathesis, resembling fulminent "black" smallpox. This suggests a potential role for therapeutic strategies developed for septic shock, in treatment of smallpox. Drugs licensed for other viruses which share molecular targets with orthopoxviruses (e.g. Cidofovir) or cancer drugs (e.g. Gleevec and other tyrosine kinase inhibitors) have immediate application for treatment of smallpox and monkeypox and provide leads for second generation drugs with higher therapeutic indices. Recent advances in identification of virulence determinants and immune evasion genes facilitate the design of alternative vaccines to replace live vaccinia strains that are unsuitable for a large proportion of individuals in a mass immunization campaign.

Rift Valley fever is considered to be one of the most important viral zoonoses in Africa. In 2000, the Rift valley fever virus spread to the Arabian Peninsula and caused two simultaneous outbreaks in Yemen and Saudi Arabia. It is transmitted to ruminants and to humans by mosquitoes. The viral agent is an arbovirus, which belongs to the Phlebovirus genus in the Bunyaviridae family. This family of viruses comprises more than 300 members grouped into five genera: Orthobunyavirus, Phlebovirus, Hantavirus, Nairovirus, and Tospovirus. Several members of the Bunyaviridae family are responsible for fatal hemorrhagic fevers: Rift Valley fever virus (Phlebovirus), Crimean-Congo hemorrhagic fever virus (Nairovirus), Hantaan, Sin Nombre and related viruses (Hantavirus), and recently Garissa, now identified as Ngari virus (Orthobunyavirus). Here are reviewed recent advances in Rift Valley fever virus, its epidemiology, molecular biology and focus on recent data on the interactions between viral and cellular proteins, which help to understand the molecular mechanisms utilized by the virus to circumvent the host cellular response.

Since the mid-1990s, West Nile virus (WNV) has emerged as a significant agent of arboviral encephalitis in several regions of the world. In 1999, WNV was introduced into the northeastern United States and was associated with an outbreak of encephalitis affecting humans, birds and horses. Subsequently, the virus has spread across the country, and across southern Canada, and in 2002 and 2003 was associated with the largest outbreaks of arboviral encephalitis recorded in the Western hemisphere. Interestingly, the more recent spread of WNV into Mexico, Central America and the Caribbean has not been associated with the high levels of clinical disease observed in North America. This review addresses the most recent results from studies investigating the molecular biology and evolution of WNV, as well as progress in the development of diagnostic and therapeutic reagents.