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Infectious
Disorders - Drug Targets
(Formerly 'Current Drug Targets - Infectious Disorders')
ISSN: 1871-5265
Infectious Disorders
– Drug Targets
Volume 7, Number 4, December 2007
Contents
Influenza Virus Pathogenesis and Drug Targets
Guest Editor: Christopher F. Basler
Editorial:
Influenza Virus Pathogenesis and Drug Targets Pp.
281
Christopher F. Basler
Influenza Viruses: Basic Biology and Potential Drug
Targets Pp. 282-293
Christopher F. Basler
[Abstract]
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 Pp. 294-303
Lucy A. Perrone and Terrence M. Tumpey
[Abstract]
Pandemic Influenza: Preventing the Emergence of NovelStrains
and Countermeasures to Ameliorate its Effects Pp.
304-317
A. Solorzano, H. Song, D. Hickman and D.R. Pérez
[Abstract]
Influenza Virus Transmission: Basic Science and Implications
for the Use of Antiviral Drugs During a Pandemic
Pp. 318-328
Anice C. Lowen and Peter Palese
[Abstract]
Influenza Virus Hemagglutinin - Structural Studies
and their Implications for the Development of Therapeutic
Approaches Pp. 329-335
James Stevens and Ruben O. Doni
[Abstract]
The Influenza Virus NS1 Protein: Inhibitor of Innate
and Adaptive Immunity Pp. 336-343
A. Fernandez-Sesma
[Abstract]
Abstracts
[Back to top]
Editorial: Influenza Virus Pathogenesis and Drug
Targets
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 Pérez):
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.
This is an understudied area of research. The tools available
to address these issues are discussed, and the impact of transmission
efficiency upon antiviral strategies is considered.
Influenza Virus Hemagglutinin – Structural studies
and their implications for the development of therapeutic
approaches (Stevens): The influenza virus hemagglutinin
(HA) protein plays critical roles in virus attachment and
entry and is the target of neutralizing antibodies. It is
thought, based on our experience in the 20th
century, that acquisition of an HA with novel antigenicity
is critical for the emergence of an influenza pandemic. Dr.
Stevens describes structural studies on the 1918 and H5 HAs
and potential strategies to block HA function.
The Influenza Virus NS1 Protein: Inhibitor of innate
and adaptive immunity (Fernandez-Sesma): Dr. Fernandez-Sesma
describes the multiple immunomodulatory functions of the NS1
protein of influenza A viruses. The NS1 proteins have multiple
mechanisms by which they inhibit type I interferon responses,
critical components of the host innate immune response to
viral infection. Recent data from Dr. Fernandez-Sesma and
colleagues also indicates that NS1 proteins modulate adaptive
immunity to infection. The NS1, while not essential for virus
replication in cell culture, is critical for virulence. Thus,
as described by Dr. Fernandez-Sesma, the NS1 is an intriguing
target for new antiviral strategies.
Christopher F. Basler, PhD
Mount Sinai School of Medicine
New York, NY
December 2007
[Back to top]
Influenza Viruses: Basic Biology and Potential Drug Targets
Christopher F. Basler
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.
[Back to top]
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
Lucy A. Perrone and Terrence M. Tumpey
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.
[Back to top]
Pandemic Influenza: Preventing the Emergence of Novel Strains
and Countermeasures to Ameliorate its Effects
A. Solorzano, H. Song, D. Hickman and D.R. Pérez
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 naïve 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.
[Back to top]
Influenza Virus Transmission: Basic Science and Implications
for the Use of Antiviral Drugs During a Pandemic
Anice C. Lowen and Peter Palese
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.
[Back to top]
Influenza Virus Hemagglutinin - Structural Studies and their
Implications for the Development of Therapeutic Approaches
James Stevens and Ruben O. Donis
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.
[Back to top]
The Influenza Virus NS1 Protein: Inhibitor of Innate and Adaptive
Immunity
A. Fernandez-Sesma
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.
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