Gamma-herpesvirus latency requires T cell evasion during episome maintenance.
The gamma-herpesviruses persist as latent episomes in a dynamic lymphocyte pool. Their consequent need to express a viral episome maintenance protein presents a potential immune target. The glycine-alanine repeat of the Epstein-Barr virus episome maintenance protein, EBNA-1, limits EBNA-1 epitope presentation to CD8(+) T lymphocytes (CTLs). However, CTL recognition occurs in vitro, so the significance of such evasion for viral fitness is unclear. We used the murine gamma-herpesvirus-68 (MHV-68) to define the in vivo contribution of cis-acting CTL evasion to host colonisation. Although the ORF73 episome maintenance protein of MHV-68 lacks a glycine-alanine repeat, it was equivalent to EBNA-1 in conferring limited presentation on linked epitopes. This was associated with reduced protein synthesis and reduced protein degradation. We bypassed the cis-acting evasion of ORF73 by using an internal ribosome entry site to express in trans-a CTL target from the same mRNA. This led to a severe, MHC class I-restricted and CTL-dependent reduction in viral latency. Thus, despite MHV-68 encoding at least two trans-acting CTL evasion proteins, cis-acting evasion during episome maintenance was essential for normal host colonisation.
Bennett
Neil J
NJ
Division of Virology, Department of Pathology, University of Cambridge, United Kingdom.
May
Janet S
JS
Stevenson
Philip G
PG
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D019309:Epstein-Barr Virus Nuclear Antigens / Q000235:genetics; D018142:Gammaherpesvirinae / Q000235:genetics* / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016366:Open Reading Frames; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000821:virology*; D017735:Virus Latency / Q000276:immunology*
D019309:Epstein-Barr Virus Nuclear Antigens; D015395:Histocompatibility Antigens Class I; C417029:EBV-encoded nuclear antigen 1