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

描述（由申请人提供）：免疫能力强的宿主对人巨细胞病毒（HCMV）感染的免疫反应存在悖论，对那些没有免疫能力的人具有潜在的破坏性后果。对保护性HCMV疫苗的长期探索受到多种因素的阻碍，包括关于HCMV自然史的两个矛盾。(1) HCMV被认为是一种在免疫能力强的宿主中具有低致病潜能的病毒。然而，在那些限制临床结果的免疫反应存在的情况下，病毒有效地维持了终身的持久性。HCMV持久性的一个标志是潜伏病毒基因组的重新激活和病毒的脱落。水平传播对有原发性HCMV感染风险的人，特别是先前没有HCMV免疫的母亲所生的胎儿，具有传染性威胁。越来越多的证据凸显了HCMV免疫的另一个模糊性。(2)初次感染和长期感染时产生的对HCMV的免疫反应，对病毒后遗症具有保护作用，但对水平传播病毒粒子的再感染不完全具有保护作用。已经确定的是，先前免疫的妇女可以再次感染HCMV抗原变异，然后传播给胎儿。本研究假设病毒与宿主的相互作用、持久性和再感染之间存在一个关键的联系，这对疫苗介导的干预是敏感的。具体来说，HCMV通过HCMV编码的白细胞介素-10蛋白（cmvIL10）的功能调节宿主免疫，使病毒再激活和病毒粒子超越再感染部位的全身传播成为可能。假设：HCMV感染者暴露后cmvIL10中和抗体（NAb）滴度增加将(1)减少HCMV的脱落(2)增加对再感染的抵抗力。本研究扩展了我们在cmvIL10的体外功能和恒河巨细胞病毒（RhCMV）编码IL-10 （rhcmvIL10）对宿主免疫的体内调节方面的工作。目的1)定量免疫功能失活的rhcmvIL10后感染RhCMV的猴子的RhCMV脱落情况。目的2)不同NAb滴度RhCMV- vil10免疫猴RhCMV再感染的比较。目的3)表征rhcmvil -10诱导的宿主免疫改变。

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. PUBLIC HEALTH RELEVANCE: The goal of this proposal is the shift the paradigm for the prevention of congenital HCMV infection by expanding the target population for an HCMV vaccine beyond just women without preconceptional HCMV immunity. Targeting those who shed virus to reduce shedding and also targeting those women with preconceptional immunity to reduce reinfection would greatly reduce the rate of congenital infection.