Pharmacologic Advances in the Treatment and Prevention of Respiratory Syncytial Virus

Empey, Kerry M.; Peebles, R. Stokes; Kolls, Jay

doi:10.1086/651603

Cited by 128 publications

(111 citation statements)

References 112 publications

(93 reference statements)

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“…There is presently no clear evidence supporting the routine use of the antiviral ribavirin (114), inhaled or systemic corticosteroids (12,87), or bronchodilators (47) as mainstays of acute therapy in nonimmunosuppressed infants and children. The humanized monoclonal anti-RSV F protein, palivizumab, is approved for prophylactic use in high-risk infants only (41,72), and thus this modality does not presently address the burden of disease among those with no apparent risk factors (55).…”

Section: Human Rsv Disease: Why Model?mentioning

confidence: 99%

Animal models of human respiratory syncytial virus disease

Reinout

Domachowske

Rosenberg

2011

American Journal of Physiology-Lung Cellular and Molecular Phys

173

228

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Bem RA, Domachowske JB, Rosenberg HF. Animal models of human respiratory syncytial virus disease. Am J Physiol Lung Cell Mol Physiol 301: L148 -L156, 2011. First published May 13, 2011; doi:10.1152/ajplung.00065.2011.-Infection with the human pneumovirus pathogen, respiratory syncytial virus (hRSV), causes a wide spectrum of respiratory disease, notably among infants and the elderly. Laboratory animal studies permit detailed experimental modeling of hRSV disease and are therefore indispensable in the search for novel therapies and preventative strategies. Present animal models include several target species for hRSV, including chimpanzees, cattle, sheep, cotton rats, and mice, as well as alternative animal pneumovirus models, such as bovine RSV and pneumonia virus of mice. These diverse animal models reproduce different features of hRSV disease, and their utilization should therefore be based on the scientific hypothesis under investigation. The purpose of this review is to summarize the strengths and limitations of each of these animal models. Our intent is to provide a resource for investigators and an impetus for future research. respiratory virus; pneumovirus; rodent; inflammation Human RSV Disease: Why Model?Human respiratory syncytial virus (hRSV) is among the most important respiratory pathogens in young children worldwide. hRSV infection and transmission result in community outbreaks with peak activity during the winter months in areas with temperate climates, whereas hRSV disease activity is observed on a more continuous basis throughout the year in tropical regions (119). In a recent evaluation of the global burden of hRSV-associated acute lower respiratory tract disease (LRTD), Nair and colleagues (82) noted that, each year, over 33 million children under the age of 5 yr are affected by this disease, leading to over 3 million hospitalizations and almost 200,000 deaths. The annual costs of health care associated with hRSV infection among children in the US alone are over $600 million (86). In addition, a growing body of evidence suggests that hRSV infection results in substantial morbidity among the elderly and in adults with underlying chronic illnesses, further highlighting both the healthcare-related and economic burden of hRSV disease (44).At this writing, there is no licensed vaccine for hRSV, and there are no specific treatment options for severe disease. There is presently no clear evidence supporting the routine use of the antiviral ribavirin (114), inhaled or systemic corticosteroids (12, 87), or bronchodilators (47) as mainstays of acute therapy in nonimmunosuppressed infants and children. The humanized monoclonal anti-RSV F protein, palivizumab, is approved for prophylactic use in high-risk infants only (41, 72), and thus this modality does not presently address the burden of disease among those with no apparent risk factors (55).Modeling human hRSV disease in vivo is an indispensable step in the search for novel therapies and preventive measures for hRSV disease. Animal models provide for t...

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Section: Human Rsv Disease: Why Model?mentioning

confidence: 99%

Animal models of human respiratory syncytial virus disease

Reinout

Domachowske

Rosenberg

2011

American Journal of Physiology-Lung Cellular and Molecular Phys

173

228

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“…However, IFN-α/β and ribavirin treatments are of relatively poor efficacy in vivo against most RNA viruses as they efficiently blunt IFN-α/β signaling through expression of virulence factors 5 and often escape ribavirin 3 . This added to the fact that ribavirin treatment is raising important toxicity issues, although it was recently approved against severe hRSV disease with controversial benefits 6 . More recently, some virus-specific treatments have been marketed, in particular against influenza virus with the development of neuraminidase inhibitors 3 .…”

Section: Introductionmentioning

confidence: 99%

High-throughput Screening for Broad-spectrum Chemical Inhibitors of RNA Viruses

Lucas‐Hourani

Munier‐Lehmann

Helynck

et al. 2014

JoVE

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RNA viruses are responsible for major human diseases such as flu, bronchitis, dengue, Hepatitis C or measles. They also represent an emerging threat because of increased worldwide exchanges and human populations penetrating more and more natural ecosystems. A good example of such an emerging situation is chikungunya virus epidemics of [2005][2006] in the Indian Ocean. Recent progresses in our understanding of cellular pathways controlling viral replication suggest that compounds targeting host cell functions, rather than the virus itself, could inhibit a large panel of RNA viruses. Some broad-spectrum antiviral compounds have been identified with host target-oriented assays. However, measuring the inhibition of viral replication in cell cultures using reduction of cytopathic effects as a readout still represents a paramount screening strategy. Such functional screens have been greatly improved by the development of recombinant viruses expressing reporter enzymes capable of bioluminescence such as luciferase. In the present report, we detail a high-throughput screening pipeline, which combines recombinant measles and chikungunya viruses with cellular viability assays, to identify compounds with a broad-spectrum antiviral profile. Video LinkThe video component of this article can be found at

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“…The only therapeutic intervention for RSV infection currently available to patients is the use of ribavirin (3), but its use is also limited because of poor efficacy and teratogenicity and the requirement of an aerosol and/or intravenous (i.v.) mode of administration in hospital settings (4). New therapeutic interventions able to lower the viral load, decrease transmission, and prevent lower respiratory complications are needed.…”

mentioning

confidence: 99%

The Interferon Type I/III Response to Respiratory Syncytial Virus Infection in Airway Epithelial Cells Can Be Attenuated or Amplified by Antiviral Treatment

McCutcheon

Jordan

Mawhorter

et al. 2016

J Virol

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Human respiratory syncytial virus (RSV) is a single-stranded RNA virus that causes acute, and occasionally fatal, lower respiratory illness in young infants, the elderly, and immunocompromised patients. Therapeutic interventions able to cut short viral replication and quickly return the airways to normal function are needed. An understanding of antiviral activities and their effects on host defense mechanisms is important for the design of safe and effective therapy. We targeted functionally and temporally distinct steps within the viral life cycle using small-molecule RSV inhibitors and studied their antiviral activities and their effects on innate interferon responses of airway epithelial cells in vitro. H uman respiratory syncytial virus (RSV) is a single-stranded, negative-sense RNA virus belonging to the family Paramyxoviridae. Premature and very young infants are at the highest risk of having severe lower respiratory tract infections and, later, a higher incidence of chronic asthma (1). Older adults with chronic lung or heart disease and individuals with suppressed immune systems also often require medical care after RSV infection. The lack of long-lasting protection after primary infection contributes to the capacity of RSV to cause yearly outbreaks and has challenged vaccine development (2). Synagis, a monoclonal antibody (MAb) directed against the RSV fusion protein, has shown prophylactic utility, but its cost and intramuscular route of administration have limited its use to hospitalized, high-risk infants Ͻ2 years of age (2). The only therapeutic intervention for RSV infection currently available to patients is the use of ribavirin (3), but its use is also limited because of poor efficacy and teratogenicity and the requirement of an aerosol and/or intravenous (i.v.) mode of administration in hospital settings (4). New therapeutic interventions able to lower the viral load, decrease transmission, and prevent lower respiratory complications are needed.RSV infection is initiated by attachment of the viral G protein to the surface of airway epithelial (AE) cells (5,6). Following attachment, the viral F protein mediates fusion of the viral and cellular membranes, allowing the RSV ribonucleic protein (RNP) complex, comprised of the viral RNA genome encapsulated with nucleoprotein (N) and associated with the phosphoprotein (P) and RNA-dependent RNA polymerase (L), to enter the cytoplasm. The RNP complex performs viral transcription to produce capped and polyadenylated mRNAs and genome replication. Detailed understanding of RSV biology is made difficult by the intimate coupling of transcription and replication activities. Furthermore, the RSV polymerase is large and complex, containing multiple domains and enzymatic activities that allow it to function and be

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Pharmacologic Advances in the Treatment and Prevention of Respiratory Syncytial Virus

Cited by 128 publications

References 112 publications

Animal models of human respiratory syncytial virus disease

Animal models of human respiratory syncytial virus disease

High-throughput Screening for Broad-spectrum Chemical Inhibitors of RNA Viruses

The Interferon Type I/III Response to Respiratory Syncytial Virus Infection in Airway Epithelial Cells Can Be Attenuated or Amplified by Antiviral Treatment

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