Infectious Disorders - Drug Targets (Formerly Current Drug Targets - Infectious Disorders) - Volume 7, Issue 4, 2007

While seasonal influenza, caused by influenza A viruses and influenza B viruses, continues to cause significant morbidity and mortality, pandemic influenza raises fears of a potentially catastrophic public health event. Two occurrences in particular have galvanized support for influenza virus research, particularly as it pertains to pandemics. The first was the identification of human cases, and particularly those resulting in human deaths, of avian influenza. Such cases were first recognized in Hong Kong in 1997, when 6 of 18 human cases of avian H5N1 influenza virus infections led to death. Despite the eradication of such viruses from the live bird markets of Hong Kong at the time, highly pathogenic avian influenza reemerged in poultry in 2004. Since 2004, H5N1 has spread from Asia, to Europe and to the Middle East and Africa. At least 327 human cases with 199 human deaths have occurred by infection from close human contact with avian species. This has raised fears of a human pandemic in which the avian-adapted H5N1 viruses either mutate to become adapted to humans or reassort their multiple genomic RNA segments with those of circulating human strains such that a virus with novel antigenicity and the capacity to efficiently spread from human to human becomes established in the human population. The second was the reconstruction of the 1918 pandemic influenza virus, a virus that killed an estimated 20-40 million people worldwide. Characterization of the fully reconstructed pandemic virus demonstrated that this was a virus with unique virulence characteristics, not typical of other human isolates. In addition to capturing the public imagination, the 1918 virus reconstruction opened up new opportunities to characterize the pathogenesis and transmission properties of highly virulent human influenza viruses. It is with this as a background that the components of this volume were conceived. The reviews that follow describe our current understanding of pandemic influenza, and focus on important new findings that have grown out of this emphasis on H5N1 and 1918 viruses. The goal of these reviews is to suggest how this new information may be employed to develop new anti-influenza virus strategies. Influenza viruses: Basic Biology and Current Antiviral Strategies (Basler): This review provides a brief overview of the biology of influenza A viruses with a particular emphasis on their molecular biology and basic epidemiology. A goal is to define the functions of the 11 known viral proteins, indicating their role in viral replication, and thereby highlight potential viral functions that might be targeted. Also discussed are the uses and limitations of the existing antivirals that target the M2 ion channel (amantadine and rimantadine) and that target the viral neuraminidase (NA) (oseltamivir and zanamavir). Reconstruction of the 1918 Pandemic Influenza Virus: How Revealing the Molecular Secrets of the Virus Responsible for the Worst Pandemic in Recorded History Can Guide Our Response to Future Influenza Pandemics (Perrone and Tumpey): Dr. Tumpey has been involved in the direct characterization of both H5N1 and 1918 influenza viruses. This article focuses on lessons learned from study of the 1918 pandemic virus and this information might be used to devise interventions for future pandemics. Pandemic Influenza: Preventing the emergence of novel strains and countermeasures to ameliorate its effects. (Solorzano, Song, Hickman and Perez): Dr. Perez reviews the role of influenza viruses that circulate in animal, primarily avian, reservoirs in the emergence of new human pandemic strains. Particular attention is paid to the ecology of avian influenza viruses, host range determinants and the potential role of other species as intermediate strains the may facilitate the reassortment of human and avian into pandemic strains. In this context, “intervention strategies” to prevent emergence of pandemic strains are discussed. Influenza Virus Transmission: Basic science and implications for the use of antiviral drugs during a pandemic (Lowen and Palese): Drs. Lowen and Palese review recently developed animal models that permit transmission of influenza viruses to be characterized. Both viral and host determinants of transmission are critical for the emergence of pandemic strains, for the persistence in humans of seasonal influenza and have important implications for antiviral strategies........

Influenza A and influenza B viruses are continuing causes of morbidity and mortality on an annual basis. Influenza A viruses have historically caused periodic pandemics in the human population, sometimes with devastating consequences, such as in 1918. Fears of a new pandemic have increased in recent years because of continuing outbreaks of highly pathogenic H5N1 avian influenza viruses in birds with occasional, but often lethal infection of humans. Despite their importance as human pathogens, the antiviral drugs approved to treat influenza virus infections are currently limited to two targets, the viral neuraminidase and the viral ion channel, M2. The use of the M2 inhibitors amantadine and rimantadine is further limited by the propensity of these drugs to select for drug resistant variants. However, the replication cycle of influenza viruses has been intensively studied and is receiving increased attention. New opportunities exist to develop novel antiviral strategies targeting these viruses.

There is an ever-present threat that a pandemic will result from the emergence of a new influenza strain to which humans have little immunity. In 1957 and 1968, new influenza viruses emerged into the human population and spread globally. Those pandemics were associated with high rates of illness and mortality, but both paled in comparison with the influenza pandemic of 1918. Reconstruction of the 1918 pandemic virus and studies to elucidate the exceptional virulence of the virus will be important steps toward understanding virulent influenza strains. One approach has been to reconstruct recombinant viruses, in which genes of the 1918 virus are replaced with genes from contemporary human influenza viruses in attempts to understand which of the eight virus gene segments contribute to its high virulence. The identification of the precise pandemic virus genes associated with replication may help elucidate virulence factors for other influenza viruses with pandemic potential and, thereby, help identify targets for drug intervention. An important role of antiviral drugs during an influenza pandemic will be to slow virus replication and subsequent spread while an appropriate vaccine is in production. The topics included in this review highlight areas of active research into the understanding of what made the 1918 pandemic influenza virus so virulent and transmissible. Such research is being done with the hope that the knowledge gained will allow the world to better prepare for and respond to future influenza pandemics.

Influenza is a seasonal disease that peaks every year in the winter months. Antigenic drift of the viral surface proteins, particularly the hemagglutinin (HA), is responsible for the virus's ability to evading the host's immune system, and for the severity of the disease. Pandemic influenza arises when an influenza virus carrying a novel HA gene enters into the naive human population, resulting in excess morbidity and mortality. Three major influenza pandemics were experienced in the last century and the emergence of a new pandemic strain is considered a matter of time. Our current understanding suggests that pandemic influenza strains arise from influenza viruses circulating in the natural reservoir, although the presence of intermediate hosts is considered essential in this process. Pigs and land-based birds have been shown to play a major role in the ecology of influenza viruses by providing an environment in which influenza viruses can change their phenotype, expand their host range, and eventually transmit to humans. In recent years, a great detail of attention has been placed on understanding the epidemiological and molecular factors that can lead to interspecies transmission of influenza viruses. In this review we will discuss the ecological and molecular aspects that lead to pandemic influenza as well as the intervention strategies at our disposal that can reduce the emergence of pandemic influenza strains and/or minimize their effects.

Recent and ongoing zoonotic infections of humans with avian influenza viruses have highlighted the importance of transmission in the development of an influenza pandemic. Despite the ability of H5N1 influenza viruses to grow to high titers and cause severe disease in human hosts, these viruses do not spread efficiently from human-to-human. The question of what viral, host and environmental factors are required to render an influenza virus transmissible has therefore become very topical. Recent work in the ferret model has suggested that receptor binding specificity is an important factor, but that the trait of human-like receptor recognition alone is not sufficient to confer a transmissible phenotype. In addition to the ferret, the guinea pig has been identified as a useful model host for transmission studies. Further research using these models is needed, toward understanding the molecular circumstances under which transmission can occur. A crucial role of antiviral drugs in mitigating an influenza pandemic will be to slow the spread of infection while an appropriate vaccine is in production. The efficacy of antivirals in preventing transmission is therefore of great importance. While the adamantanes, amantadine and rimantadine, have been found to fail in this respect due to the high transmissibility of drug resistant variants, the neuraminidase inhibitors, oseltamivir and zanamivir, show more promise. Anti-influenza drugs in development which show efficacy in terms of mitigating disease or viral growth should also be tested for their potential to block transmission.

Possible adaptation of one of the currently circulating strains of highly pathogenic H5N1 avian influenza A virus to produce the next human influenza pandemic is an area of major global concern. Intense research is being focused on developing new generations of effective vaccines and antivirals. Here, we discuss the structure of hemagglutinin and its potential as a target for development of future therapeutics to mitigate the impact of any future influenza pandemic.

The influenza virus NS1 protein has been shown to be a multifunctional immune modulator and a virulence factor for this virus. Among its multiple functions are the inhibition of the type I interferon (IFN) system in infected cells, the binding and sequestration of dsRNA, the interference with the host mRNA processing, the facilitation of preferential viral mRNA translation, and the inhibition of dendritic cell (DC) activation. The combination of all these functions makes the NS1 protein a very potent inhibitor of immunity and allows influenza virus to efficiently escape the immune surveillance and to establish infection in the host. There are different domains in the NS1 protein that are required for specific functions, which provides several potential targets for the action of antiviral drugs. Additionally, the crystal structure of both the N-terminal RNA binding domain and the C-terminal effector domain of the NS1 protein have been resolved, potentially allowing for better antiviral drug design. Recent advances in the understanding how viruses are detected by infected cells are unveiling the mechanisms by which the NS1 protein can perform some of its multiple immune modulating activities. In this review the multiple functions of the NS1 protein are discussed and several possible options for drug targets within the influenza virus NS1 protein will be explored. Such drugs could make influenza viruses less efficient at evading the immune system in the host.