Vaccine-mediated Targeting of Viral IL10 to Control HCMV Shedding and Reinfection

描述（由申请方提供）：免疫活性宿主对人巨细胞病毒（HCMV）感染的免疫应答存在矛盾，对无免疫活性的宿主具有潜在的破坏性后果。对保护性HCMV疫苗的长期追求受到多种因素的阻碍，包括HCMV自然史的两个矛盾。(1)HCMV被认为是在免疫活性宿主中具有低致病潜力的病毒。然而，在存在限制临床结果的那些免疫应答的情况下，病毒有效地维持终身持续性。HCMV持久性的标志是潜伏病毒基因组的再活化和病毒的脱落。水平传播对那些有原发性HCMV感染风险的人，特别是由先前没有HCMV免疫的母亲所生的胎儿构成感染威胁。越来越多的证据突出了HCMV免疫的另一个模糊性。(2)在初次和长期感染期间产生的对HCMV的免疫应答，其保护免受病毒后遗症，不完全保护免受水平传播的病毒粒子的再感染。已经确定的是，具有先前免疫力的妇女可以再次感染HCMV的抗原变体，然后可以传播给她们的胎儿。该提议假设存在连接病毒-宿主相互作用、持久性和再感染的关键联系，其易受疫苗介导的干预。具体而言，HCMV通过HCMV编码的白细胞介素-10蛋白（cmvIL 10）的功能性调节宿主免疫力，使病毒再活化和病毒体的全身扩散超出再感染部位。假设：在HCMV感染的个体中，暴露后对cmvIL 10的中和抗体（NAb）滴度的增加将（1）减少HCMV脱落和（2）增加对再感染的抗性。这项研究扩展了我们的工作cmvIL 10的体外功能和恒河猴CMV（RhCMV）编码的IL-10（rhcmvIL 10）在体内调节宿主免疫。目的1）在用功能上无活性的rhcmvIL 10免疫后，定量RhCMV感染的猴中的RhCMV脱落。目的2）比较RhCMV免疫猴对rhcmvIL 10的NAb滴度不同的猴再感染RhCMV的情况。目的3）研究rhcmvIL-10对宿主免疫功能的影响。

DESCRIPTION (provided by applicant): Immune responses to human cytomegalovirus (HCMV) infection in immunocompetent hosts present paradoxes with potentially devastating ramifications for those without immune competency. The long quest for a protective HCMV vaccine has been impeded by multiple factors, including two contradictions about HCMV natural history. (1) HCMV is considered to be a virus with low disease potential in immunocompetent hosts. Yet, the virus efficiently maintains a lifelong persistence in the presence of those immune responses that limit clinical outcomes. A hallmark of HCMV persistence is the reactivation of latent viral genomes and shedding of virus. Horizontal transmission represents an infectious threat to those at-risk for primary HCMV infection, particularly fetuses borne by mothers without prior HCMV immunity. Accumulating evidence highlights another ambiguity about HCMV immunity. (2) The immune responses to HCMV generated during primary and long-term infection, which protect against viral sequelae, are incompletely protective against reinfection with horizontally transmitted virions. It is well- established that women with prior immunity can be reinfected with antigenic variants of HCMV that can then be transmitted to their fetuses. This proposal hypothesizes that there is a key nexus linking virus-host interactions, persistence, and reinfection that is susceptible to vaccine- mediated intervention. Specifically, HCMV modulation of host immunity through the functionality of the HCMV-encoded interleukin-10 protein (cmvIL10), enables both viral reactivation and systemic spread of virions beyond sites of reinfection. HYPOTHESIS: post-exposure increases of neutralizing antibody (NAb) titers to cmvIL10 in HCMV-infected individuals will (1) reduce HCMV shedding and (2) increase resistance to reinfection. This study extends our work on the in vitro functionality of cmvIL10 and the in vivo modulation of host immunity by rhesus CMV (RhCMV)-encoded IL-10 (rhcmvIL10). Aim 1) Quantification of RhCMV shedding in RhCMV- infected monkeys following immunization with functionally inactive rhcmvIL10. Aim 2) Comparison of RhCMV reinfection in RhCMV-immune monkeys that differ in their NAb titers to rhcmvIL10. Aim 3) Characterization of rhcmvIL-10-induced alterations to host immunity.