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

• DOI: 10.1128/jvi.77.13.7696-7701.2003
• Publication Date: 2003-06-13T00:18:39Z
• Authors: Scott A. Tibbetts; Joy Loh; Victor van Berkel; James S. McClellan; Meagan A. Jacoby; Sharookh B. Kapadia; Samuel H. Speck; Herbert W. Virgin
• Keywords: 0301 basic medicine; Mice; 03 medical and health sciences; Gammaherpesvirinae; Animals; Herpesviridae Infections; Virus Latency; 3. Good health

ABSTRACT

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 10 6 PFU of murine gammaherpesvirus 68 (γHV68) and quantitatively measured latency and acute-phase replication. Surprisingly, during latency, the frequencies of ex vivo reactivation were similar over a 10 7 -fold range of doses for i.p. infection and over a 10 4 -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 γHV68 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.