Gammaherpesviruses (GHVs) establish life-long infections and cause cancer in humans and other animals. To facilitate chronic infection, GHV oncoproteins promote cellular proliferation and differentiation. Aberrant cell-cycle progression driven by viral oncogenes should trigger activation of tumor suppressor p53, unless p53 is functionally deactivated during GHV latency establishment. However, interactions of GHVs with the p53 pathway during the establishment and maintenance of latent infection are poorly defined. Here we demonstrate in vivo that p53 is induced specifically in infected cells during latency establishment by murine gammaherpesvirus 68 (MHV68). In the absence of p53, MHV68 latency establishment was significantly increased, especially in germinal center B cells, and correlated with enhanced cellular proliferation. However, enhanced latency was not sustainable, and MHV68 exhibited a defect in long-term latency maintenance in p53-deficient mice. Moreover, IgH/c-Myc translocations were readily detected in B cells from infected p53-null mice indicating virus-driven genomic instability. These data demonstrate that p53 intrinsically restricts MHV68 latency establishment and reveal a paradigm in which a host restriction factor provides a long-term benefit to a chronic pathogen by limiting infection-associated damage.

中文翻译：

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p53控制鼠γ疱疹病毒潜伏期并防止感染相关的IgH / c-Myc易位

伽马疱疹病毒（GHV）建立了终生感染，并在人类和其他动物中引发癌症。为了促进慢性感染，GHV癌蛋白促进细胞增殖和分化。病毒致癌基因驱动的异常细胞周期进程应触发肿瘤抑制因子p53的激活，除非在GHV潜伏期建立过程中p53功能失活。但是，在潜伏感染的建立和维持过程中，GHV与p53途径的相互作用尚不明确。在这里，我们在体内证明了在小鼠γ疱疹病毒68（MHV68）潜伏期建立过程中，p53在感染细胞中被特异性诱导。在没有p53的情况下，MHV68潜伏期的建立显着增加，尤其是在生发中心B细胞中，并与增强的细胞增殖相关。然而，增强的潜伏期是不可持续的，并且MHV68在p53缺陷小鼠的长期潜伏期维持中表现出缺陷。此外，在感染的p53-null小鼠的B细胞中很容易检测到IgH / c-Myc易位，表明病毒驱动的基因组不稳定。这些数据表明，p53本质上限制了MHV68潜伏期的建立，并揭示了一种范例，其中宿主限制因子通过限制感染相关的损害为慢性病原体提供了长期利益。