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Gamma-herpesvirus latency requires T cell evasion during episome maintenance.

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Bennett, Neil J 
May, Janet S 
Stevenson, Philip G 


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.



Animals, CD8-Positive T-Lymphocytes, Epstein-Barr Virus Nuclear Antigens, Gammaherpesvirinae, Histocompatibility Antigens Class I, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Open Reading Frames, T-Lymphocytes, Cytotoxic, Virus Latency

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PLoS Biol

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Public Library of Science (PLoS)
Medical Research Council (G9800943)