Gammaherpesviruses infect lymphocytes and cause lymphocytic cancers. Murid herpesvirus-4 (MuHV-4), Epstein-Barr virus, and Kaposi's sarcoma-associated herpesvirus all infect B cells. Latent infection can spread by B cell recirculation and proliferation, but whether this alone achieves systemic infection is unclear. To test the need of MuHV-4 for lytic infection in B cells, we flanked its essential ORF50 lytic transactivator with loxP sites and then infected mice expressing B cell-specific Cre (CD19-Cre). The floxed virus replicated normally in Cre⁻ mice. In CD19-Cre mice, nasal and lymph node infections were maintained; but there was little splenomegaly, and splenic virus loads remained low. Cre-mediated removal of other essential lytic genes gave a similar phenotype. CD19-Cre spleen infection by intraperitoneal virus was also impaired. Therefore, MuHV-4 had to emerge lytically from B cells to colonize the spleen. An important role for B cell lytic infection in host colonization is consistent with the large CD8⁺ T cell responses made to gammaherpesvirus lytic antigens during infectious mononucleosis and suggests that vaccine-induced immunity capable of suppressing B cell lytic infection might reduce long-term virus loads.

IMPORTANCE Gammaherpesviruses cause B cell cancers. Most models of host colonization derive from cell cultures with continuous, virus-driven B cell proliferation. However, vaccines based on these models have worked poorly. To test whether proliferating B cells suffice for host colonization, we inactivated the capacity of MuHV-4, a gammaherpesvirus of mice, to reemerge from B cells. The modified virus was able to colonize a first wave of B cells in lymph nodes but spread poorly to B cells in secondary sites such as the spleen. Consequently, viral loads remained low. These results were consistent with virus-driven B cell proliferation exploiting normal host pathways and thus having to transfer lytically to new B cells for new proliferation. We conclude that viral lytic infection is a potential target to reduce B cell proliferation.

伽玛疱疹病毒感染淋巴细胞并导致淋巴细胞癌。Murid herpesvirus-4 (MuHV-4)、Epstein-Barr 病毒和卡波西肉瘤相关疱疹病毒都感染 B 细胞。潜伏感染可通过 B 细胞再循环和增殖传播，但仅此一项是否会实现全身感染尚不清楚。为了测试 MuHV-4 对 B 细胞裂解感染的需求，我们将其必需的 ORF50 裂解反式激活因子与loxP位点连接，然后感染表达 B 细胞特异性 Cre (CD19-Cre) 的小鼠。floxed 病毒在 Cre 中正常复制^-老鼠。在 CD19-Cre 小鼠中，鼻和淋巴结感染得以维持；但几乎没有脾肿大，脾病毒载量仍然很低。Cre 介导的其他必需裂解基因的去除产生了类似的表型。腹膜内病毒引起的 CD19-Cre 脾脏感染也受损。因此，MuHV-4 必须从 B 细胞中溶解出来以在脾脏中定殖。B 细胞溶解性感染在宿主定植中的重要作用与传染性单核细胞增多症期间对 γ 疱疹病毒溶解性抗原的大 CD8 ⁺ T 细胞反应一致，并表明能够抑制 B 细胞溶解性感染的疫苗诱导免疫可能会减少长期病毒载量.

重要性伽玛疱疹病毒会导致 B 细胞癌。大多数宿主定植模型源自具有持续的、病毒驱动的 B 细胞增殖的细胞培养物。然而，基于这些模型的疫苗效果不佳。为了测试增殖的 B 细胞是否足以进行宿主定植，我们灭活了小鼠的伽马疱疹病毒 MuHV-4 从 B 细胞中重新出现的能力。修改后的病毒能够在淋巴结中的第一波 B 细胞中定殖，但在脾脏等二级部位的 B 细胞中传播不良。因此，病毒载量仍然很低。这些结果与利用正常宿主途径的病毒驱动的 B 细胞增殖一致，因此必须裂解性地转移到新的 B 细胞以进行新的增殖。我们得出结论，病毒溶解感染是减少 B 细胞增殖的潜在目标。