title: Adenovirus-based vaccines against rhesus lymphocryptovirus EBNA-1 induce expansion of specific CD8+ and CD4+ T cells in persistently infected rhesus macaques.
abstract: The impact of Epstein-Barr virus (EBV) on human health is substantial, but vaccines that prevent primary EBV infections or treat EBV-associated diseases are not yet available. The Epstein-Barr nuclear antigen 1 (EBNA-1) is an important target for vaccination because it is the only protein expressed in all EBV-associated malignancies. We have designed and tested two therapeutic EBV vaccines that target the rhesus (rh) lymphocryptovirus (LCV) EBNA-1 to determine if ongoing T cell responses during persistent rhLCV infection in rhesus macaques can be expanded upon vaccination. Vaccines were based on two serotypes of E1-deleted simian adenovirus and were administered in a prime-boost regimen. To further modulate the response, rhEBNA-1 was fused to herpes simplex virus glycoprotein D (HSV-gD), which acts to block an inhibitory signaling pathway during T cell activation. We found that vaccines expressing rhEBNA-1 with or without functional HSV-gD led to expansion of rhEBNA-1-specific CD8(+) and CD4(+) T cells in 33% and 83% of the vaccinated animals, respectively. Additional animals developed significant changes within T cell subsets without changes in total numbers. Vaccination did not increase T cell responses to rhBZLF-1, an immediate early lytic phase antigen of rhLCV, thus indicating that increases of rhEBNA-1-specific responses were a direct result of vaccination. Vaccine-induced rhEBNA-1-specific T cells were highly functional and produced various combinations of cytokines as well as the cytolytic molecule granzyme B. These results serve as an important proof of principle that functional EBNA-1-specific T cells can be expanded by vaccination.
  
  
  OBJECTIVE
  EBV is a common human pathogen that establishes a persistent infection through latency in B cells, where it occasionally reactivates. EBV infection is typically benign and is well controlled by the host adaptive immune system; however, it is considered carcinogenic due to its strong association with lymphoid and epithelial cell malignancies. Latent EBNA-1 is a promising target for a therapeutic vaccine, as it is the only antigen expressed in all EBV-associated malignancies. The goal was to determine if rhEBNA-1-specific T cells could be expanded upon vaccination of infected animals. Results were obtained with vaccines that target EBNA-1 of rhLCV, a virus closely related to EBV. We found that vaccination led to expansion of rhEBNA-1 immune cells that exhibited functions fit for controlling viral infection. This confirms that rhEBNA-1 is a suitable target for therapeutic vaccines. Future work should aim to generate more-robust T cell responses through modified vaccines.
authors: The Wistar Institute, Philadelphia, Pennsylvania, USA.
authors: R
authors: R
authors: Leskowitz
authors: M H
authors: MH
authors: Fogg
authors: X Y
authors: XY
authors: Zhou
authors: A
authors: A
authors: Kaur
authors: E L V
authors: EL
authors: Silveira
authors: F
authors: F
authors: Villinger
authors: P M
authors: PM
authors: Lieberman
authors: F
authors: F
authors: Wang
authors: H C
authors: HC
authors: Ertl
mesh_terms: D000261:Adenoviruses, Simian / Q000235:genetics; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D004337:Drug Carriers; D005260:Female; D005822:Genetic Vectors; D006566:Herpesviridae Infections / Q000276:immunology / Q000662:veterinary*; D022283:Herpesvirus Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D018143:Lymphocryptovirus / Q000235:genetics / Q000276:immunology*; D008253:Macaca mulatta; D014611:Vaccination / Q000379:methods; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology*
chemical_list: D004337:Drug Carriers; D022283:Herpesvirus Vaccines; D014764:Viral Proteins