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Journal of Virology, July 2002, p. 6532-6544, Vol. 76, No. 13
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.13.6532-6544.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Characterization of a Spontaneous 9.5-Kilobase-Deletion Mutant of Murine Gammaherpesvirus 68 Reveals Tissue-Specific Genetic Requirements for Latency

Eric T. Clambey,1,2 Herbert W. Virgin, IV,2* and Samuel H. Speck1*

Division of Microbiology and Immunology, Yerkes Regional Primate Research Center, Emory University, Atlanta, Georgia 30329,1 Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 631102

Received 17 January 2002/ Accepted 29 March 2002

Murine gammaherpesvirus 68 ({gamma}HV68 [also known as MHV-68]) establishes a latent infection in mice, providing a small-animal model with which to identify host and viral factors that regulate gammaherpesvirus latency. While {gamma}HV68 establishes a latent infection in multiple tissues, including splenocytes and peritoneal cells, the requirements for latent infection within these tissues are poorly defined. Here we report the characterization of a spontaneous 9.5-kb-deletion mutant of {gamma}HV68 that lacks the M1, M2, M3, and M4 genes and eight viral tRNA-like genes. Previously, this locus has been shown to contain the latency-associated M2, M3, and viral tRNA-like genes. Through characterization of this mutant, we found that the M1, M2, M3, M4 genes and the viral tRNA-like genes are dispensable for (i) in vitro replication and (ii) the establishment and maintenance of latency in vivo and reactivation from latency following intraperitoneal infection. In contrast, following intranasal infection with this mutant, there was a defect in splenic latency at both early and late times, a phenotype not observed in peritoneal cells. These results indicate (i) that there are different genetic requirements for the establishment of latency in different latent reservoirs and (ii) that the genetic requirements for latency depend on the route of infection. While some of these phenotypes have been observed with specific mutations in the M1 and M2 genes, other phenotypes have never been observed with the available {gamma}HV68 mutants. These studies highlight the importance of loss-of-function mutations in defining the genetic requirements for the establishment and maintenance of herpesvirus latency.

* Corresponding author. Mailing address for S. H. Speck: Division of Microbiology and Immunology, Yerkes Regional Primate Research Center, 954 Gatewood Rd., N.E., Atlanta, GA 30329. Phone: (404) 727-7665. Fax: (404) 727-7768. E-mail: sspeck{at}rmy.emory.edu. Mailing address for H. W. Virgin IV: Department of Pathology and Immunology, Washington University, 660 S. Euclid Ave., St. Louis, MO 63110. Phone: (314) 362-9223. Fax: (314) 362-4096. E-mail: virgin{at}immunology.wustl.edu.

Journal of Virology, July 2002, p. 6532-6544, Vol. 76, No. 13
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.13.6532-6544.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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