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A Single CD8+ T Cell Epitope Sets the Long-Term Latent Load of a Murid Herpesvirus 1,2 1,2 3 1,2 Sofia Marques , Marta Alenquer , Philip G. Stevenson , J. Pedro Simas * ˆ 1 Instituto de Microbiologia e Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal, 2 Instituto Gulbenkian de Ciencia, Oeiras, Portugal, 3 Division of Virology, Department of Pathology, University of Cambridge, Cambridge, United Kingdom Abstract The pathogenesis of persistent viral infections depends critically on long-term viral loads. Yet what determines these loads is largely unknown. Here, we show that a single CD8+ T cell epitope sets the long-term latent load of a lymphotropic gamma- herpesvirus, Murid herpesvirus-4 (MuHV-4). The MuHV-4 M2 latency gene contains an H2-Kd -restricted T cell epitope, and wild-type but not M22 MuHV-4 was limited to very low level persistence in H2d mice. Mutating the epitope anchor residues increased viral loads and re-introducing the epitope reduced them again. Like the Kaposi’s sarcoma–associated herpesvirus K1, M2 shows a high frequency of non-synonymous mutations, suggesting that it has been selected for epitope loss. In vivo competition experiments demonstrated directly that epitope presentation has a major impact on viral fitness. Thus, host MHC class I and viral epitope expression interact to set the long-term virus load. Citation: Marques S, Alenquer M, Stevenson PG, Simas JP (2008) A Single CD8+ T Cell Epitope Sets the Long-Term Latent Load of a Murid Herpesvirus. PLoS Pathog 4(10): e1000177. doi:10.1371/journal