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

Ron Geller,Raul Andino,Judith Frydman,Luis Menéndez-Arias

doi:10.1371/journal.pone.0056762

Abstract

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.

Highlights

Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory infections
To examine whether RSV is dependent on Hsp90 activity, we tested the effect of 2 clinically relevant Hsp90 inhibitors, 17AAG and 17DMAG, on the replication of RSV in HEp-2 cells
We first established the sensitivity of uninfected HEp-2 cells to these Hsp90 inhibitors to obtain a range of drug concentrations that is appropriate for testing antiviral activity (Figure 1A, B)

Summary

Introduction

Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory infections. RSV is recognized as an important pathogen in the elderly, where it leads to 170,000 infections and 10,000 deaths in the US alone [2]. No RSV vaccine is currently available; the development of such a vaccine presents significant challenges due to the difficulties associated with inducing immune responses in infants and the elderly [3,4]. No effective antivirals are available to combat RSV infections [5,6]. Prophylactic treatment with monoclonal antibodies has been shown to be effective against RSV, their use remains cost prohibitive and limited to high-risk infants [5,6]. The identification of novel antivirals for treatment of RSV infections remains a top priority

Methods

Results

Conclusion