title: A gamma-herpesvirus deficient in replication establishes chronic infection in vivo and is impervious to restriction by adaptive immune cells.
abstract: Chronic gamma-herpesvirus infection is a dynamic process involving latent infection, reactivation from latency, and low level persistent replication. The gamma-herpesviruses maintain latent infection in restricted subsets of hematopoietic cells as a result of an intricate balance between host factors that suppress infection and viral factors that facilitate evasion of the immune response. Immune effectors limit reactivation and subsequent replication events, and the adaptive immune response ultimately restricts infection to a level compatible with life-long infection. However, it has not been possible to determine whether the immune system constrains chronic infection by directly targeting latently infected cells in vivo due to the complex nature of chronic infection. To begin to address this issue, we generated a murine gamma-herpesvirus 68 (gammaHV68) deficient in its ability to replicate or undergo reactivation from latency via a mutation in the single-stranded DNA binding protein encoded by ORF6. Even in the absence of lytic replication, this virus established long-term infection in peritoneal cells of wild-type mice at levels identical to that of wild-type gammaHV68, and generated an immune response that was sufficient to protect against secondary challenge with wild-type gammaHV68. Nevertheless, the number of latently infected cells was not significantly altered in mice deficient in T cells or both T cells and B cells, demonstrating that the adaptive immune system is incapable of altering infection with a virus lacking the capacity for lytic replication and reactivation from latency. Thus, these data support the conclusion that latency is immunologically silent.
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, 660 S. Euclid, Box 8118, St. Louis, MO 63110, USA. stibbe@lsuhsc.edu
authors.forename: Scott A
authors.initials: SA
authors.lastname: Tibbetts
authors.forename: Felipe
authors.initials: F
authors.lastname: Suarez
authors.forename: Ashley L
authors.initials: AL
authors.lastname: Steed
authors.forename: Jacob A
authors.initials: JA
authors.lastname: Simmons
authors.forename: Herbert W
authors.initials: HW
authors.lastname: Virgin
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D002908:Chronic Disease; D018142:Gammaherpesvirinae / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D006566:Herpesviridae Infections / Q000276:immunology*; D007109:Immunity / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D041681:NIH 3T3 Cells; D013601:T-Lymphocytes / Q000276:immunology; D017735:Virus Latency; D014779:Virus Replication / Q000235:genetics / Q000502:physiology*