Immune control of the number and reactivation phenotype of cells latently infected with a gammaherpesvirus.
Despite active immune responses, gammaherpesviruses establish latency. In a related process, these viruses also persistently replicate by using a mechanism that requires different viral genes than acute-phase replication. Many questions remain about the role of immunity in chronic gammaherpesvirus infection, including whether the immune system controls latency by regulating latent cell numbers and/or other properties and what specific immune mediators control latency and persistent replication. We show here that CD8(+) T cells regulate both latency and persistent replication and demonstrate for the first time that CD8(+) T cells regulate both the number of latently infected cells and the efficiency with which infected cells reactivate from latency. Furthermore, we show that gamma interferon (IFN-gamma) and perforin, which play no significant role during acute infection, are essential for immune control of latency and persistent replication. Surprisingly, the effects of perforin and IFN-gamma are site specific, with IFN-gamma being important in peritoneal cells while perforin is important in the spleen. Studies of the mechanisms of action of IFN-gamma and perforin revealed that perforin acts primarily by controlling the number of latently infected cells while IFN-gamma acts primarily by controlling reactivation efficiency. The immune system therefore controls chronic gammaherpesvirus infection by site-specific mechanisms that regulate both the number and reactivation phenotype of latently infected cells.
Tibbetts
Scott A
SA
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
van Dyk
Linda F
LF
Speck
Samuel H
SH
Virgin
Herbert W
HW
D000818:Animals; D016827:CD8 Antigens / Q000235:genetics / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002908:Chronic Disease; D018142:Gammaherpesvirinae / Q000254:growth & development / Q000276:immunology / Q000502:physiology*; D006566:Herpesviridae Infections / Q000276:immunology* / Q000821:virology; D007371:Interferon-gamma / Q000172:deficiency / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D014775:Virus Activation / Q000276:immunology*; D017735:Virus Latency / Q000276:immunology*; D014779:Virus Replication
D016827:CD8 Antigens; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D054353:Perforin; D007371:Interferon-gamma