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.
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.
|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|
|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|
|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|
|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|
|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|
|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|