Hsp90 Inhibitors Exhibit Resistance-Free Antiviral Activity against Respiratory Syncytial Virus

Geller, Ron; Andino, Raul; Frydman, Judith
February 2013
PLoS ONE;Feb2013, Vol. 8 Issue 2, p1
Academic Journal
Respiratory syncytial virus (RSV) is a major cause of respiratory illness in young children, leading to significant morbidity and mortality worldwide. Despite its medical importance, no vaccine or effective therapeutic interventions are currently available. Therefore, there is a pressing need to identify novel antiviral drugs to combat RSV infections. Hsp90, a cellular protein-folding factor, has been shown to play an important role in the replication of numerous viruses. We here demonstrate that RSV requires Hsp90 for replication. Mechanistic studies reveal that inhibition of Hsp90 during RSV infection leads to the degradation of a viral protein similar in size to the RSV L protein, the viral RNA-dependent RNA polymerase, implicating it as an Hsp90 client protein. Accordingly, Hsp90 inhibitors exhibit antiviral activity against laboratory and clinical isolates of RSV in both immortalized as well as primary differentiated airway epithelial cells. Interestingly, we find a high barrier to the emergence of drug resistance to Hsp90 inhibitors, as extensive growth of RSV under conditions of Hsp90 inhibition did not yield mutants with reduced sensitivity to these drugs. Our results suggest that Hsp90 inhibitors may present attractive antiviral therapeutics for treatment of RSV infections and highlight the potential of chaperone inhibitors as antivirals exhibiting high barriers to development of drug resistance.


Related Articles

  • Administration of Palivizumab: A Medical Provider's Perspective. Helm, Elizabeth A.; Cummings, Ginny E.; Keane, Virginia; King Jr., James C. // Clinical Pediatrics;Nov/Dec2003, Vol. 42 Issue 9, p821 

    Describes a clinical experience in administering palivizumab in children with respiratory syncytial virus infection. Dose administration; Mechanism of action; Costs related to injection visits for palivizumab prophylaxis.

  • Extracellular Hsp72, an endogenous DAMP, is released by virally infected airway epithelial cells and activates neutrophils via Toll-like receptor (TLR)-4. Wheeler, Derek S.; Chase, Margaret A.; Albert P.Senft; Sue E Poynter; Wong, Hector R.; Page, Kristen // Respiratory Research;2009, Vol. 10, p1 

    Background: Neutrophils play an important role in the pathophysiology of RSV, though RSV does not appear to directly activate neutrophils in the lower airways. Therefore locally produced cytokines or other molecules released by virally-infected airway epithelial cells are likely responsible for...

  • Respiratory syncytial virus: disease, development and treatment. Banning, Maggi // British Journal of Nursing;7/27/2006, Vol. 15 Issue 14, p751 

    Respiratory syncytial virus (RSV) is spread by droplets and causes infections of the upper and lower respiratory tract. It is most common in infants, children under the age of five years and the elderly. Due to the nature of the transmission, infections with RSV are contagious but usually short...

  • Predicting the Severity of Bronchiolitis in a Resource-poor Setting. Drolia, Anil; Dewan, Pooja; Gupta, Piyush // Internet Journal of Pediatrics & Neonatology;2009, Vol. 11 Issue 1, p14 

    Introduction: Bronchiolitis is the leading acute viral infection in infants. Early diagnosis and determination of severity of bronchiolitis in children is crucial for rapid initiation of treatment. This may be difficult to achieve in a resource-poor setting, where laboratory support and...

  • Mortality in children from influenza and respiratory syncytial virus. Fleming, Douglas M.; Pannell, Rachel S.; Cross, Kenneth W. // Journal of Epidemiology & Community Health;Jul2005, Vol. 59 Issue 7, p586 

    Study objective: To quantify mortality attributable to influenza and respiratory syncytial virus (RSV) infection in children. Design and methods: Comparison of death rates (all cause and certified respiratory) in England over winters 1989/90 to 1999/00 during and outside influenza and RSV...

  • This new drug may help prevent RSV disease. Cerrato, Paul L. // RN;Jun96, Vol. 59 Issue 6, p69 

    Reports on the development of the plasma-derived antibody called RespiGam for the prevention of respiratory syncytial virus (RSV) disease.

  • Nasally administered Lactobacillus rhamnosus strains differentially modulate respiratory antiviral immune responses and induce protection against respiratory syncytial virus infection. Tomosada, Yohsuke; Chiba, Eriko; Zelaya, Hortensia; Takahashi, Takuya; Tsukida, Kohichiro; Kitazawa, Haruki; Alvarez, Susana; Villena, Julio // BMC Immunology;2013, Vol. 14 Issue 1, p1 

    Background: Some studies have shown that nasally administered immunobiotics had the potential to improve the outcome of influenza virus infection. However, the capacity of immunobiotics to improve protection against respiratory syncytial virus (RSV) infection was not investigated before....

  • Inhibition of respiratory syncytial virus infection with intranasal siRNA nanoparticles targeting the viral NS1 gene. Zhang, Weidong; Yang, Hong; Kong, Xiaoyuan; Mohapatra, Subhra; Juan-Vergara, Homero San; Hellermann, Gary; Behera, Sumita; Singam, Rajeswari; Lockey, Richard F; Mohapatra, Shyam S // Nature Medicine;Jan2005, Vol. 11 Issue 1, p56 

    Respiratory syncytial virus (RSV) infection is one of the major causes of respiratory tract infection for which no vaccine or antiviral treatment is available. The RSV NS1 protein seems to antagonize the host interferon (IFN) response; however, its mechanism is unknown. Here, we used a...

  • Synagis.  // Royal Society of Medicine: Medicines;2002, p520 

    The article presents information on the antiviral drug synagis developed by Abbott Pharmaceuticals. This drug is a proprietary, prescription-only preparation of the drug palivizumab, which can be used to treat viral infection caused by respiratory syncytial virus. It is available in a form for...


Read the Article


Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics