Respiratory syncytial virus (RSV) is the most important etiologic agent of pediatric viral respiratory infection and remains a major cause of morbidity and mortality among infants as well as immunocompromised subjects and the elderly. Long-term effects of severe RSV infection during infancy include wheezing and asthma later in life. Currently, there is no licensed vaccine for RSV, nor are there effective curative treatments for severe RSV disease. Prophylactic injection of anti-RSV immunoglobulin (palivizumab) is used for high-risk individuals clinically, although the cost- effectiveness of this treatment is unclear. Thus, there is a pressing need to develop robust antiviral therapies for RSV. We have recently shown that inhibition of the Akt signal transduction pathway reduced RSV replication, in addition to the replication of a number of other non-segmented negative- sense RNA viruses, in cultured cells. We propose to determine the potential for targeting Akt to treat severe RSV infection by focusing on following specific aims: 1) determine how signaling through the Akt pathway affects RSV replication;and 2) define the mechanism by which Akt inhibition blocks RSV replication. These studies will allow us to identify and characterize a host protein thats is a novel drug target for the inhibition of RSV replication. Akt inhibitors have been used in the pre-clinical trials as anti-cancer treatments and have been shown to be safe and effective. Thus, we hypothesize that similar Akt inhibitors can be used both prophylactically and therapeutically to prevent the development of severe RSV disease in a safe and efficacious manner. In addition, understanding how Akt inhibitors block RSV replication may allow us to define a specific pathway necessary for paramyxovirus replication in general, allowing the development of broad spectrum antiviral therapeutics that are effective against an array of human viral diseases.

Public Health Relevance

Respiratory syncytial virus is the leading cause of pediatric viral illness. Currently, the only effective antiviral treatment to prevent RSV infection is prophylactic injection of monoclonal antibody to RSV F protein;however, the cost-effectiveness of this treatment is under debate. We are proposing to identify and characterize a novel drug target of RSV that can potentially be used both prophylactically and therapeutically in a clinical setting.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Drug Discovery and Mechanisms of Antimicrobial Resistance Study Section (DDR)
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Kim, Sonnie
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Pennsylvania State University
Schools of Arts and Sciences
University Park
United States
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Whelan, Jillian N; Reddy, Krishna D; Uversky, Vladimir N et al. (2016) Functional correlations of respiratory syncytial virus proteins to intrinsic disorder. Mol Biosyst 12:1507-26
Whelan, Jillian N; Tran, Kim C; van Rossum, Damian B et al. (2016) Identification of Respiratory Syncytial Virus Nonstructural Protein 2 Residues Essential for Exploitation of the Host Ubiquitin System and Inhibition of Innate Immune Responses. J Virol 90:6453-6463
Bajorek, M; Caly, L; Tran, K C et al. (2014) The Thr205 phosphorylation site within respiratory syncytial virus matrix (M) protein modulates M oligomerization and virus production. J Virol 88:6380-93
Phan, Shannon I; Chen, Zhenhai; Xu, Pei et al. (2014) A respiratory syncytial virus (RSV) vaccine based on parainfluenza virus 5 (PIV5). Vaccine 32:3050-7
Webster Marketon, Jeanette I; Corry, Jacqueline; Teng, Michael N (2014) The respiratory syncytial virus (RSV) nonstructural proteins mediate RSV suppression of glucocorticoid receptor transactivation. Virology 449:62-9
Tian, Bing; Zhao, Yingxin; Kalita, Mridul et al. (2013) CDK9-dependent transcriptional elongation in the innate interferon-stimulated gene response to respiratory syncytial virus infection in airway epithelial cells. J Virol 87:7075-92
Fuentes, Sandra; Crim, Roberta L; Beeler, Judy et al. (2013) Development of a simple, rapid, sensitive, high-throughput luciferase reporter based microneutralization test for measurement of virus neutralizing antibodies following Respiratory Syncytial Virus vaccination and infection. Vaccine 31:3987-94
Wu, Weining; Tran, Kim C; Teng, Michael N et al. (2012) The interactome of the human respiratory syncytial virus NS1 protein highlights multiple effects on host cell biology. J Virol 86:7777-89
Hotard, Anne L; Shaikh, Fyza Y; Lee, Sujin et al. (2012) A stabilized respiratory syncytial virus reverse genetics system amenable to recombination-mediated mutagenesis. Virology 434:129-36
Sun, Qi; Wu, Runzhi; Cai, Sutang et al. (2011) Synthesis and biological evaluation of analogues of AKT (protein kinase B) inhibitor-IV. J Med Chem 54:1126-39