γ疱疹病毒感染大多数脊椎动物物种,并与B细胞淋巴瘤有关。操纵B细胞分化对于由γ疱疹病毒驱动的自然感染和淋巴生成至关重要。具体来说,人类爱泼斯坦-巴尔病毒(EBV)和鼠γ疱疹病毒68(MHV68)驱动感染的幼稚B细胞分化为生发中心,以在慢性感染建立过程中实现潜伏病毒储库的指数增加。感染的生发中心B细胞也是病毒淋巴发生的目标,因为大多数EBV阳性B细胞淋巴瘤具有生发中心反应的特征。所有γ疱疹病毒都编码一种蛋白激酶,which,在卡波西肉瘤相关疱疹病毒(KSHV)和MHV68的情况下,是足够和必要的,分别,驱动体内B细胞分化。在这项研究中,我们使用高度可处理的慢性γ疱疹病毒感染的MHV68模型揭示了MHV68蛋白激酶与干扰素调节因子1(IRF-1)之间的拮抗关系.IRF-1缺乏对体内无激酶MHV68的裂解复制减弱的影响最小。相比之下,在IRF-1-/-小鼠中,激酶无效的MHV68的减弱的潜伏储库被部分完全挽救,以及完全抢救MHV68驱动的生发中心反应。因此,新型病毒蛋白激酶-IRF-1拮抗作用主要限于以病毒潜伏期为主的慢性感染,与急性感染期间和体外裂解复制的相关性较小.鉴于病毒和宿主蛋白的保守性,两者之间的对立,根据这项研究的定义,可以调节跨物种的γ疱疹病毒感染。重要性γ疱疹病毒是操纵生理B细胞分化以建立终身感染的流行病原体。这种操作也涉及γ疱疹病毒驱动的B细胞淋巴瘤,作为潜伏感染的B细胞的分化,通过生发中心反应靶向这些转化。在这项研究中,我们定义了一种保守的γ疱疹病毒蛋白激酶与宿主抗病毒和肿瘤抑制转录因子之间的新型拮抗相互作用。在这项研究中揭示的病毒-宿主拮抗作用对于塑造γ疱疹病毒驱动的生发中心反应的程度至关重要。相比之下,病毒-宿主拮抗作用与体外和体内急性感染期间的裂解病毒复制关系不大,强调了新兴的概念,即非重叠机制决定了急性和慢性γ疱疹病毒感染的参数。
Gammaherpesviruses infect most vertebrate species and are associated with B cell lymphomas. Manipulation of B cell differentiation is critical for natural infection and lymphomagenesis driven by gammaherpesviruses. Specifically, human Epstein-Barr virus (EBV) and murine gammaherpesvirus 68 (MHV68) drive differentiation of infected naive B cells into the germinal center to achieve exponential increase in the latent viral reservoir during the establishment of chronic infection. Infected germinal center B cells are also the target of viral lymphomagenesis, as most EBV-positive B cell lymphomas bear the signature of the germinal center response. All gammaherpesviruses encode a protein kinase, which, in the case of Kaposi\'s sarcoma-associated herpesvirus (KSHV) and MHV68, is sufficient and necessary, respectively, to drive B cell differentiation in vivo. In this study, we used the highly tractable MHV68 model of chronic gammaherpesvirus infection to unveil an antagonistic relationship between MHV68 protein kinase and interferon regulatory factor 1 (IRF-1). IRF-1 deficiency had minimal effect on the attenuated lytic replication of the kinase-null MHV68 in vivo. In contrast, the attenuated latent reservoir of the kinase-null MHV68 was partially to fully rescued in IRF-1-/- mice, along with complete rescue of the MHV68-driven germinal center response. Thus, the novel viral protein kinase-IRF-1 antagonism was largely limited to chronic infection dominated by viral latency and was less relevant for lytic replication during acute infection and in vitro. Given the conserved nature of the viral and host protein, the antagonism between the two, as defined in this study, may regulate gammaherpesvirus infection across species. IMPORTANCE Gammaherpesviruses are prevalent pathogens that manipulate physiological B cell differentiation to establish lifelong infection. This manipulation is also involved in gammaherpesvirus-driven B cell lymphomas, as differentiation of latently infected B cells through the germinal center response targets these for transformation. In this study, we define a novel antagonistic interaction between a conserved gammaherpesvirus protein kinase and a host antiviral and tumor suppressor transcription factor. The virus-host antagonism unveiled in this study was critically important to shape the magnitude of gammaherpesvirus-driven germinal center response. In contrast, the virus-host antagonism was far less relevant for lytic viral replication in vitro and during acute infection in vivo, highlighting the emerging concept that nonoverlapping mechanisms shape the parameters of acute and chronic gammaherpesvirus infection.