Impact of immune senescence on herpes zoster in a nonhuman primate model

描述（由申请人提供）： 潜伏水痘带状疱疹病毒（VZV）的重新激活导致带状疱疹（HZ，也称为带状疱疹），这是一种在老年人中引起主要发病率和偶尔死亡率的疾病。HZ的发病率从40-49岁的3.3/1000人-年增加到60-69岁的7.7/1000人-年。高龄不仅是发展HZ的主要危险因素，也是并发症如带状疱疹后神经痛、血管病变和带状疱疹眼。目前的估计预测，到2020年，超过7000万美国人将超过65岁，因此，HZ和相关并发症的发病率肯定会增加。此外，目前批准的HZ疫苗仅将带状疱疹的发病率降低了51%。因此，很大一部分疫苗接种者仍然对VZV再激活敏感。开发更好的HZ治疗方法和疫苗的一个主要障碍是，利用VZV感染实验室动物的模型不会产生人类临床疾病的迹象。因此，由于缺乏合适的动物模型来研究体内宿主-病原体相互作用，我们对VZV感染和再活化的免疫保护相关性的理解仍然非常有限。 我们已经开发了一种非人灵长类动物模型，其中感染了人VZV的灵长类同源物猴水痘病毒（SVV）的年轻恒河猴显示出人VZV感染的特征;即，全身水痘皮疹的出现、细胞和体液免疫的发展以及感觉神经节中具有有限转录活性的潜伏期的建立。与年轻的恒河猴相反，感染SVV的老年动物保持持续的病毒血症。在老年猴中，尽管IgG抗体反应的发展与年轻动物产生的反应相当，但仍发生持续的裂解复制。另一方面，与年轻动物产生的SVV特异性T细胞应答相比，老年动物中SVV特异性T细胞应答显著延迟。这些数据有力地表明，如对VZV所述，老年动物中T细胞应答的缺陷导致SVV复制和传播的免疫控制不良。这一假设的进一步证据是从耗尽CD 4或CD 8 T细胞然后感染SVV的年轻恒河猴中获得的。在CD 8 T细胞耗竭的动物中，尽管存在与非耗竭对照相当的IgG应答，但在肺中持续检测到SVV抗原。在CD 4 T细胞耗尽的动物中，IgG应答显著延迟和降低。然而，尽管IgG滴度在一只CD 4 T细胞耗尽的动物中达到与对照相当的水平，但它仍然保持持续的病毒血症。这些数据有力地表明，如针对VZV所述，稳健的T细胞应答的发展和维持对于SVV感染的控制至关重要。因此，年轻和老年恒河猴的SVV感染提供了一个独特的机会：（1）确定SVV特异性T细胞应答中的年龄相关差异和（2）确定这些免疫应答差异如何影响老年动物控制SVV复制和维持潜伏期的能力。这些研究将提高我们对潜伏性VZV以及对老年人造成重大健康问题的其他潜伏性病原体的免疫控制的理解。 公共卫生相关性：带状疱疹（HZ）或带状疱疹是由潜伏的水痘带状疱疹病毒（VZV）的再活化引起的，并且在老年人中引起显著的发病率，有时甚至死亡。虽然人们普遍认为T细胞免疫力下降是HZ的根本原因，但具体缺陷仍然知之甚少。在本申请中，我们将采用一种新的和强大的VZV感染的非人灵长类动物模型，以提高我们对老年人VZV免疫控制的理解，这是设计更好的疫苗和治疗以预防老年人HZ和其他潜伏病原体的先决条件。

DESCRIPTION (provided by applicant): Reactivation of latent varicella zoster virus (VZV) leads to herpes zoster (HZ, also known as shingles), a disease that causes major morbidity and occasionally mortality in older individuals. The incidence of HZ increases from 3.3 per 1000 person-years at age 40-49 to 7.7 at age 60-69. Advanced age is the primary risk factor not only for developing HZ, but also complications such as post herpetic neuralgia, vasculopathies and zoster opthalmicus. Current estimates predict that by 2020 more than 70 million Americans will be over the age of 65 therefore, the incidence of HZ and associated complications will certainly increase. Furthermore, the currently approved vaccine against HZ reduces the incidence of shingles by only 51%. Thus, a significant portion of the vaccine recipients still remains susceptible to VZV reactivation. A major obstacle in developing better treatments and vaccines for HZ is that models utilizing VZV infection of laboratory animals do not produce signs of in clinical disease that occur in humans. Consequently, our understanding of the immune correlates of protection against VZV infection and reactivation remains very limited due to lack of a suitable animal model to study host-pathogen interactions in vivo. We have developed a nonhuman primate model wherein young rhesus macaques infected with a primate homologue of human VZV, simian varicella virus (SVV) display the hallmarks of VZV infection in humans; i.e., the appearance of generalized varicella rash, the development of cellular and humeral immunity, and the establishment of latency with limited transcriptional activity in sensory ganglia. In contrast to young rhesus macaques, aged animals infected with SVV remain persistently viremic. In aged monkeys, persistent lytic replication occurred despite the development of an IgG antibody response that was comparable to that generated by young animals. On the other hand, SVV-specific T cell responses in aged animals were significantly delayed compared to those generated by young animals. These data strongly suggest that, as described for VZV, defects in T cell responses in aged animals result in poor immunological control of SVV replication and dissemination. Further evidence for this hypothesis was obtained from young rhesus macaques depleted of either CD4 or CD8 T cells and then infected with SVV. In CD8 T cell-depleted animals, SVV antigen was persistently detected in the lungs despite presence of a comparable IgG response to non-depleted controls. In CD4 T cell-depleted animals, the IgG response was significantly delayed and reduced. However, although IgG titers reached comparable levels as the controls in one CD4 T cell-depleted animal, it remained persistently viremic nevertheless. These data strongly suggest that, as described for VZV, the development and maintenance of a robust T cell response is critical to the control of SVV infection. Therefore, SVV infection of young and aged rhesus macaques provides a unique opportunity to: (1) identify age-related differences in the SVV-specific T cell responses and (2) determine how these differences in immune responses affect the aged animal's ability to control SVV replication and to maintain latency. These studies will improve our understanding of immunological control of latent VZV as well as other latent pathogens that pose significant health issues for the elderly. PUBLIC HEALTH RELEVANCE: Herpes zoster (HZ), or shingles, is caused by reactivation of latent varicella zoster virus (VZV) and causes significant morbidity and sometimes mortality in the elderly. Although it is generally believed that decreased T cell immunity is the underlying cause of HZ, the specific defects remain poorly understood. In this application, we will employ a novel and robust nonhuman primate model of VZV infection to improve our understanding of the immune control of VZV in the aged, a prerequisite for designing better vaccines and treatment to prevent HZ and other latent pathogens in the elderly.