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 M2− 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.
Highlights
Since the pool of latent genomes is constantly drained by viral reactivation, it must be replenished by virus-driven lymphoproliferation; this in turn is limited by host T cells; the steady-state viral load reflects an equilibrium of these fluxes
As most EpsteinBarr virus (EBV) studies are necessarily descriptive, the murid gamma-herpesvirus Murid herpesvirus-4 (MuHV-4) provides an important focus of pathogenesis research
We find a major role for a single MHC class I–restricted latency epitope
Summary
Since the pool of latent genomes is constantly drained by viral reactivation, it must be replenished by virus-driven lymphoproliferation; this in turn is limited by host T cells; the steady-state viral load reflects an equilibrium of these fluxes. Viral loads are remarkably constant in one individual, yet vary hugely between them [1]. Murid herpesvirus-4 (MuHV-4) is one of the best established. It is genetically closer to Kaposi’s sarcoma associated herpesvirus (KSHV) than to EpsteinBarr virus (EBV), but shares with EBV a lymphoproliferative infectious mononucleosis syndrome [2] and persistence in memory B cells [3,4,5]. The steady state MuHV-4 latent load does not appear to reflect the inoculating virus dose [6], suggesting that it is set instead by host and viral genetic polymorphisms
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