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Journal of Virology, June 2002, p. 5866-5874, Vol. 76, No. 12
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.12.5866-5874.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

High-Frequency Intermolecular Homologous Recombination during Herpes Simplex Virus-Mediated Plasmid DNA Replication

Xinping Fu,1 Hua Wang,1 and Xiaoliu Zhang1,2*

Center for Cell and Gene Therapy,1 Departments of Pediatrics, Molecular Virology, and Microbiology, Baylor College of Medicine, Houston, Texas 770302

Received 27 November 2001/ Accepted 18 March 2002

Homologous recombination is a prominent feature of herpes simplex virus (HSV) type 1 DNA replication. This has been demonstrated and traditionally studied in experimental settings where repeated sequences are present or are being introduced into a single molecule for subsequent genome isomerization. In the present study, we have designed a pair of unique HSV amplicon plasmids to examine in detail intermolecular homologous recombination (IM-HR) between these amplicon plasmids during HSV-mediated DNA replication. Our data show that IM-HR occurred at a very high frequency: up to 60% of the amplicon concatemers retrieved from virion particles underwent intermolecular homologous recombination. Such a high frequency of IM-HR required that both plasmids be replicated by HSV-mediated replication, as IM-HR events were not detected when either one or both plasmids were replicated by simian virus 40-mediated DNA replication, even with the presence of HSV infection. In addition, the majority of the homologous recombination events resulted in sequence replacement or targeted gene repair, while the minority resulted in sequence insertion. These findings imply that frequent intermolecular homologous recombination may contribute directly to HSV genome isomerization. In addition, HSV-mediated amplicon replication may be an attractive model for studying intermolecular homologous recombination mechanisms in general in a mammalian system. In this regard, the knowledge obtained from such a study may facilitate the development of better strategies for targeted gene correction for gene therapy purposes.

* Corresponding author. Mailing address: Department of Pediatrics and Center for Cell and Gene Therapy, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. Phone: (713) 798-1256. Fax: (713) 798-1230. E-mail: xzhang{at}bcm.tmc.edu.

Journal of Virology, June 2002, p. 5866-5874, Vol. 76, No. 12
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.12.5866-5874.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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