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Journal of Virology, February 2009, p. 1402-1415, Vol. 83, No. 3
0022-538X/09/$08.00+0     doi:10.1128/JVI.01138-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

SOCS-1 Mimetics Protect Mice against Lethal Poxvirus Infection: Identification of a Novel Endogenous Antiviral System {triangledown}

Chulbul M. Ahmed,{dagger}* Rea Dabelic,{dagger} Lilian W. Waiboci, Lindsey D. Jager, Linda L. Heron, and Howard M. Johnson

Department of Microbiology and Cell Science, University of Florida, P.O. Box 110700, Gainesville, Florida 32611-0700

Received 30 May 2008/ Accepted 7 November 2008

The suppressor of cytokine signaling 1 (SOCS-1) protein modulates cytokine signaling by binding to and inhibiting the function of Janus kinases (JAKs), ErbB, and other tyrosine kinases. We have developed a small tyrosine kinase inhibitor peptide (Tkip) that binds to the autophosphorylation site of tyrosine kinases and inhibits activation of STAT transcription factors. We have also shown that a peptide corresponding to the kinase-inhibitory region of SOCS-1, SOCS1-KIR, similarly interacts with the activation loop of JAK2 and blocks STAT activation. Poxviruses activate cellular tyrosine kinases, such as ErbB-1 and JAK2, in the infection of cells. We used the pathogenesis of vaccinia virus in C57BL/6 mice to determine the ability of the SOCS-1 mimetics to protect mice against lethal vaccinia virus infection. Injection of mice intraperitoneally with Tkip or SOCS1-KIR containing a palmitate for cell penetration, before and at the time of intranasal challenge with 2 x 106 PFU of vaccinia virus, resulted in complete protection at 100 µg. Initiation of treatment 1 day postinfection resulted in 80% survival. Administration of SOCS-1 mimetics by the oral route also protected mice against lethal effects of the virus. Both SOCS1-KIR and Tkip inhibited vaccinia virus transcription and replication at early and possibly later stages of infection. Vaccinia virus-induced phosphorylation of ErbB-1 and JAK2 was inhibited by the mimetics. Protected mice mounted a strong humoral and cellular response to vaccinia virus. The use of SOCS-1 mimetics in the treatment of poxvirus infections reveals an endogenous regulatory system that previously was not known to have an antiviral function.

* Corresponding author. Mailing address: Department of Microbiology and Cell Science, University of Florida, P.O. Box 110700, Gainesville, FL 32611-0700. Phone: (352) 392-6883. Fax: (352) 392-5922. E-mail: ahmed1{at}ufl.edu

{triangledown} Published ahead of print on 19 November 2008.

{dagger} These authors contributed equally to this work.

Journal of Virology, February 2009, p. 1402-1415, Vol. 83, No. 3
0022-538X/09/$08.00+0     doi:10.1128/JVI.01138-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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