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Journal of Virology, July 2003, p. 7696-7701, Vol. 77, No. 13
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.13.7696-7701.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Establishment and Maintenance of Gammaherpesvirus Latency Are Independent of Infective Dose and Route of Infection

Scott A. Tibbetts,1 Joy Loh,1 Victor van Berkel,1 James S. McClellan,1 Meagan A. Jacoby,2 Sharookh B. Kapadia,1 Samuel H. Speck,2* and Herbert W. Virgin IV1*

Department of Pathology and Immunology and Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri 63110,1 Division of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia 303292

Received 21 January 2003/ Accepted 28 March 2003

Gammaherpesviruses such as Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus are important human pathogens that establish long-term latent infections. Understanding of the initiation and maintenance of latent infections has important implications for the prevention and treatment of gammaherpesvirus-related diseases. Although much is known about gammaherpesvirus pathogenesis, it is unclear how the infectious dose of a virus influences its ability to establish latent infection. To examine the relationship between the infectious dose and gammaherpesvirus latency, we inoculated wild-type mice with 0.01 to 106 PFU of murine gammaherpesvirus 68 ({gamma}HV68) and quantitatively measured latency and acute-phase replication. Surprisingly, during latency, the frequencies of ex vivo reactivation were similar over a 107-fold range of doses for i.p. infection and over a 104-fold range of doses for intranasal infection. Further, the frequencies of cells harboring viral genome during latency did not differ substantially over similar dose ranges. Although the kinetics of acute-phase replication were delayed at small doses of virus, the peak titer did not differ significantly between mice infected with a large dose of virus and those infected with a small dose of virus. The results presented here indicate that any initiation of infection leads to substantial acute-phase replication and subsequent establishment of a maximal level of latency. Thus, infections with doses as small as 0.1 PFU of {gamma}HV68 result in stable levels of acute-phase replication and latent infection. These results demonstrate that the equilibrium level of establishment of gammaherpesvirus latency is independent of the infectious dose and route of infection.

* Corresponding author. Mailing address for H.W.V.: Department of Pathology and Immunology, Washington University School of Medicine, 660 S. Euclid, Box 8118, St. Louis, MO 63110. Phone: (314) 362-9223. Fax: (314) 362-4096. E-mail: virgin{at}immunology.wustl.edu. Mailing address for S.H.S.: Division of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University, 954 Gatewood Rd., N.E., Atlanta, GA 30329. Phone: (404) 727-7665. Fax: (404) 727-1488. E-mail: sspeck{at}rmy.emory.edu.

Journal of Virology, July 2003, p. 7696-7701, Vol. 77, No. 13
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.13.7696-7701.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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Copyright © 2003 by the American Society for Microbiology. All rights reserved.