Nennig Kylie, Shaw Teressa, Borsinger Logan, Bailey Adam L
Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, USA.
J Virol. 2025 Jun 17;99(6):e0024825. doi: 10.1128/jvi.00248-25. Epub 2025 May 8.
Viruses that establish persistent (i.e., chronic) infections have evolved sophisticated strategies to avoid clearance by the host immune system. This is particularly true for viruses that infect immunocompetent mammals and sustain high infectious burdens in body sites under intense immune surveillance (i.e., the blood, a.k.a., "viremia"). Historically, lymphocytic choriomeningitis virus (LCMV) infection of laboratory mice has served as a powerful model to understand mechanisms of failed immunity, but other viruses may have unique and underappreciated persistence strategies. Here, we resurrect a bygone model of viral persistence-lactate dehydrogenase-elevating virus (LDV)-and use modern transgenic mouse technologies to investigate various aspects of anti-viral immunity. We find that interferons have a modest impact on LDV replication, with interferon-alpha blunting LDV viremia in the acute phase of the infection and interferon-gamma reducing LDV viral loads in the chronic phase of infection, but only when paired with an intact interferon-alpha response. Adaptive immunity, assessed in Rag-knockout mice, had only a modest impact on LDV viremia, and only during the sub-acute phase of infection. Mice lacking the critical immune checkpoint molecule PD-1 showed no signs of disease and supported LDV viral loads at levels equivalent to their wild-type counterparts. Altogether, these results point to a novel and highly effective mechanism of persistence that is minimally impacted by conventional aspects of anti-viral immunity or immune exhaustion-a rarity among persistent viruses. Given the relative paucity of chronic infection models in the laboratory mouse, LDV infection may be useful for exploring unique modes of immune system failure.
Viruses that infect a host over long periods of time have evolved unique strategies to evade the host immune system. Of particular interest are viruses that cause persistent infection in the laboratory mouse-the most well-developed tool for studying the mammalian immune system. Here, we resurrected a model of persistent RNA virus infection (lactate dehydrogenase-elevating virus, LDV) and applied modern tools of mouse immunology to further characterize its persistence. We found that host factors that typically have a dramatic effect on viral infections-e.g., the interferon system and lymphocytes-had very little impact on LDV infection. Removing "checks" on immune activation also had little effect on the virus or host health. Altogether, these findings imply that LDV uses a unique and highly effective mechanism to avoid immune clearance. Understanding this mechanism has implications for understanding ways in which the immune system fails.
能够建立持续性（即慢性）感染的病毒已经进化出复杂的策略来逃避宿主免疫系统的清除。对于感染具有免疫能力的哺乳动物并在受到强烈免疫监视的身体部位（即血液，又称“病毒血症”）维持高感染负荷的病毒来说尤其如此。从历史上看，实验室小鼠感染淋巴细胞性脉络丛脑膜炎病毒（LCMV）一直是理解免疫失败机制的有力模型，但其他病毒可能有独特且未被充分认识的持续性感染策略。在这里，我们复兴了一种过去的病毒持续性感染模型——乳酸脱氢酶升高病毒（LDV），并使用现代转基因小鼠技术来研究抗病毒免疫的各个方面。我们发现，干扰素对LDV复制有一定影响，其中α干扰素在感染急性期抑制LDV病毒血症，γ干扰素在感染慢性期降低LDV病毒载量，但这仅在与完整的α干扰素反应配对时才会发生。在Rag基因敲除小鼠中评估的适应性免疫对LDV病毒血症只有一定影响，且仅在感染亚急性期。缺乏关键免疫检查点分子PD - 1的小鼠没有疾病迹象，其支持的LDV病毒载量水平与野生型小鼠相当。总之，这些结果表明存在一种新型且高效的持续性感染机制，该机制受抗病毒免疫或免疫耗竭的传统方面影响极小——这在持续性病毒中很罕见。鉴于实验室小鼠中慢性感染模型相对较少，LDV感染可能有助于探索免疫系统失败的独特模式。
长期感染宿主的病毒已经进化出独特的策略来逃避宿主免疫系统。特别令人感兴趣的是那些在实验室小鼠（研究哺乳动物免疫系统最完善的工具）中引起持续性感染的病毒。在这里，我们复兴了一种持续性RNA病毒感染模型（乳酸脱氢酶升高病毒，LDV），并应用现代小鼠免疫学工具进一步表征其持续性感染。我们发现，通常对病毒感染有显著影响的宿主因素，如干扰素系统和淋巴细胞，对LDV感染影响很小。去除对免疫激活的“检查”对病毒或宿主健康也几乎没有影响。总之，这些发现意味着LDV使用一种独特且高效的机制来避免免疫清除。理解这一机制对于理解免疫系统失败的方式具有重要意义。
