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Journal of Virology, February 2002, p. 1790-1801, Vol. 76, No. 4
0022-538X/01/$04.00+0     DOI: 10.1128/JVI.76.4.1578-1587.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Disruption of the M2 Gene of Murine Gammaherpesvirus 68 Alters Splenic Latency following Intranasal, but Not Intraperitoneal, Inoculation

Meagan A. Jacoby,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,1 Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri2

Received 6 August 2001/ Accepted 18 November 2001

Infection of mice with murine gammaherpesvirus 68 ({gamma}HV68; also referred to as MHV68) provides a tractable small-animal model with which to address the requirements for the establishment and maintenance of gammaherpesvirus infection in vivo. The M2 gene of {gamma}HV68 is a latency-associated gene that encodes a protein lacking discernible homology to any known viral or cellular proteins. M2 gene transcripts have been detected in latently infected splenocytes (S. M. Husain, E. J. Usherwood, H. Dyson, C. Coleclough, M. A. Coppola, D. L. Woodland, M. A. Blackman, J. P. Stewart, and J. T. Sample, Proc. Natl. Acad. Sci. USA 96:7508-7513, 1999; H. W. Virgin IV, R. M. Presti, X. Y. Li, C. Liu, and S. H. Speck, J. Virol. 73:2321-2332, 1999) and peritoneal exudate cells (H. W. Virgin IV, R. M. Presti, X. Y. Li, C. Liu, and S. H. Speck, J. Virol. 73:2321-2332, 1999), as well as in a latently {gamma}HV68-infected B-lymphoma cell line (S. M. Husain, E. J. Usherwood, H. Dyson, C. Coleclough, M. A. Coppola, D. L. Woodland, M. A. Blackman, J. P. Stewart, and J. T. Sample, Proc. Natl. Acad. Sci. USA 96:7508-7513, 1999). Here we describe the generation of {gamma}HV68 mutants with disruptions in the M2 gene. Mutation of the M2 gene did not affect the ability of the virus to replicate in tissue culture, nor did it affect {gamma}HV68 virulence in B6.Rag1 deficient mice. However, we found that M2 was differentially required for acute replication in vivo. While mutation of M2 did not affect acute phase of virus replication in the lungs of mice following intranasal inoculation, acute-phase virus replication in the spleen was decreased compared to that of the wild-type and marker rescue viruses following intraperitoneal inoculation. Upon intranasal inoculation, M2 mutant viruses exhibited a significant decrease in the establishment of latency in the spleen on day 16 postinfection, as measured by the frequency of viral genome-positive cells. In addition, M2 mutant viral genome-positive cells reactivated from latency inefficiently compared to wild-type and marker rescue viruses. By day 42 after intranasal inoculation, the frequencies of M2 mutant and wild-type viral genome-positive cells were nearly equivalent and little reactivation was detected from either population. In sharp contrast to the results obtained following intranasal inoculation, after intraperitoneal inoculation, no significant defect was observed in the establishment or reactivation from latency with the M2 mutant viruses. These results indicate that the requirements for the establishment of latency are affected by the route of infection.

* Corresponding author. Mailing address for Samuel H. Speck: Division of Microbiology and Immunology, Yerkes Regional Primate Research Center, Emory University School of Medicine, 954 Gatewood Rd. N.E., Atlanta, GA 30329. Phone: (404) 727-9917. Fax: (404) 727-7768. E-mail: sspeck{at}00400064rmy.emory.edu. Mailing address for Herbert W. Virgin IV: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63130. Phone: (314) 362-9223. Fax: (314) 362-4096. E-mail: virgin{at}immunology.wustl.edu.

Journal of Virology, February 2002, p. 1790-1801, Vol. 76, No. 4
0022-538X/01/$04.00+0     DOI: 10.1128/JVI.76.4.1578-1587.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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