Spontaneous and Engineered Compensatory HSV Mutants that Counteract the Host Antiviral PKR Response 英文参考文献.docVIP

Viruses 2009, 1, 510-522; doi:10.3390/v1030510 OPEN ACCESS viruses ISSN 1999-4915 /journal/viruses Review Spontaneous and Engineered Compensatory HSV Mutants that Counteract the Host Antiviral PKR Response Amish C. Shah 1, Jacqueline N. Parker 2, Masako Shimamura 2 and Kevin A. Cassady 2,* 1 University of Pennsylvania, Department of Pediatrics, Childrens Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Philadelphia, PA 19104-4399, USA; E-Mail: amishamish@ (A.C.S.) 2 University of Alabama at Birmingham, Department of Pediatrics, Division of Infectious Disease, 1600 6th Avenue South, CHB 118C, Birmingham, AL 35222, USA; E-Mails: jnparker@ (J.N.P.); mshimamura@ (M.S.) * Author to whom correspondence should be addressed; E-Mail: kcassady@; Tel.: +1-205-996-7910; Fax: +1-205-934-0460. Received: 24 August 2009; in revised form: 22 October 2009 / Accepted: 22 October 2009 / Published: 22 October 2009 Abstract: A virulent recombinant HSV lacking the diploid ?134.5 gene (??134.5) have been investigated over the last two decades both for anti-tumor therapy and as vaccine vectors. The first generation vectors, while safe, are incapable of sustained replication in the majority of treated patients. An interferon inducible host antiviral kinase, protein kinase R (PKR), limits late viral protein synthesis and replication of ??134.5 viruses. This review describes the development of new ??134.5 vectors, through serial passage selection and direct viral genome engineering, which demonstrate selective PKR evasion in targeted cells and improved viral replication without restoring neurovirulence. Keywords: PKR; oncolytic HSV; ??134.5 1. Introduction Serial passage is a time-honored viral laboratory method that has been used to select progeny with attenuating mutations (e.g. OKA vaccine strain from varicella zoster virus). In recent years, serial passaging has been used as a method to identify secondary