Marques Sofia, Alenquer Marta, Stevenson Philip G, Simas J Pedro
Instituto de Microbiologia e Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
PLoS Pathog. 2008 Oct;4(10):e1000177. doi: 10.1371/journal.ppat.1000177. Epub 2008 Oct 10.
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.
持续性病毒感染的发病机制严重依赖于长期病毒载量。然而，决定这些载量的因素在很大程度上尚不清楚。在此，我们表明单个CD8 + T细胞表位决定了嗜淋巴细胞性γ-疱疹病毒——鼠疱疹病毒4型（MuHV-4）的长期潜伏载量。MuHV-4 M2潜伏基因包含一个H2-Kd限制性T细胞表位，野生型而非M2（-）MuHV-4在H2d小鼠中局限于非常低水平的持续存在。突变表位锚定残基会增加病毒载量，而重新引入该表位会再次降低病毒载量。与卡波西肉瘤相关疱疹病毒K1一样，M2显示出高频非同义突变，表明它已被选择用于表位缺失。体内竞争实验直接证明表位呈递对病毒适应性有重大影响。因此，宿主MHC I类分子和病毒表位表达相互作用以设定长期病毒载量。
