Manipulation of host cellular pathways is a strategy employed by gammaherpesviruses, including mouse gammaherpesvirus 68 (MHV68), in order to negotiate a chronic infection. Ataxia-telangiectasia mutated (ATM) plays a unique yet incompletely understood role in gammaherpesvirus infection, as it has both proviral and antiviral effects. Chronic gammaherpesvirus infection is poorly controlled in a host with global ATM insufficiency, whether the host is a mouse or a human. In contrast, ATM facilitates replication, reactivation, and latency establishment of several gammaherpesviruses in vitro, suggesting that ATM is proviral in the context of infected cell cultures. The proviral role of ATM is also evident in vivo, as myeloid-specific ATM expression facilitates MHV68 reactivation during the establishment of viral latency. In order to better understand the complex relationship between host ATM and gammaherpesvirus infection, we depleted ATM specifically in B cells, a cell type critical for chronic gammaherpesvirus infection. B cell-specific ATM deficiency attenuated the establishment of viral latency due to compromised differentiation of ATM-deficient B cells. Further, we found that during long-term infection, peritoneal B-1b, but not related B-1a, B cells display the highest frequency of gammaherpesvirus infection. While ATM expression did not affect gammaherpesvirus tropism for B-1 B cells, B cell-specific ATM expression was necessary to support viral reactivation from peritoneal cells during long-term infection. Thus, our study reveals a role of ATM as a host factor that promotes chronic gammaherpesvirus infection of B cells.

IMPORTANCE Gammaherpesviruses infect a majority of the human population and are associated with cancer, including B cell lymphomas. ATM is a unique host kinase that has both proviral and antiviral roles in the context of gammaherpesvirus infection. Further, there is insufficient understanding of the interplay of these roles in vivo during chronic infection. In this study, we show that ATM expression by splenic B cells is required for efficient establishment of gammaherpesvirus latency. We also show that ATM expression by peritoneal B cells is required to facilitate viral reactivation during long-term infection. Thus, our study defines a proviral role of B cell-specific ATM expression during chronic gammaherpesvirus infection.

操纵宿主细胞途径是伽马疱疹病毒（包括小鼠伽马疱疹病毒 68 (MHV68)）采用的策略，以应对慢性感染。共济失调毛细血管扩张突变 (ATM) 在伽马疱疹病毒感染中发挥着独特但尚未完全了解的作用，因为它具有前病毒和抗病毒作用。慢性伽玛疱疹病毒感染在整体 ATM 不足的宿主中很难得到控制，无论该宿主是小鼠还是人类。相比之下，ATM在体外促进几种伽马疱疹病毒的复制、重新激活和潜伏期建立，这表明 ATM 在受感染的细胞培养物中具有前病毒性。 ATM 的前病毒作用在体内也很明显，因为骨髓特异性 ATM 表达在病毒潜伏期建立期间促进 MHV68 重新激活。为了更好地了解宿主 ATM 与伽马疱疹病毒感染之间的复杂关系，我们专门在 B 细胞（一种对慢性伽马疱疹病毒感染至关重要的细胞类型）中去除了 ATM。由于 ATM 缺陷 B 细胞的分化受损，B 细胞特异性 ATM 缺陷减弱了病毒潜伏期的建立。此外，我们发现，在长期感染过程中，腹膜B-1b（而不是相关的B-1a）B细胞显示出伽玛疱疹病毒感染的频率最高。虽然 ATM 表达不影响 B-1 B 细胞的伽马疱疹病毒趋向性，但 B 细胞特异性 ATM 表达对于支持长期感染期间腹膜细胞的病毒再激活是必要的。因此，我们的研究揭示了 ATM 作为促进 B 细胞慢性伽马疱疹病毒感染的宿主因子的作用。

重要性伽马疱疹病毒感染大多数人群，并与癌症（包括 B 细胞淋巴瘤）相关。 ATM 是一种独特的宿主激酶，在伽马疱疹病毒感染中具有前病毒和抗病毒作用。此外，对于慢性感染期间这些作用在体内的相互作用还没有足够的了解。在这项研究中，我们发现脾 B 细胞表达 ATM 是有效建立伽马疱疹病毒潜伏期所必需的。我们还表明，腹膜 B 细胞表达 ATM 是促进长期感染期间病毒重新激活所必需的。因此，我们的研究定义了慢性伽马疱疹病毒感染期间 B 细胞特异性 ATM 表达的前病毒作用。