Enhancing RhCMV/SIV Vector Efficacy

两项非人类灵长类动物功效研究令人信服地证明，野生型(Wt)CMV/SIV 载体可以1)再次感染CMV+恒河猴(RM)，2)在再次感染期间，诱导有效和持久的SIV- 特异性的CD4+和CD8+T细胞反应，具有强烈的“效应记忆”(TEM)偏向，以及3)完全 保护约50%接种疫苗的RM在限制剂量直肠攻击后免受进行性SIV感染 高致病性、嗜CCR5的SIVmac239病毒。在这些RM中显示的保护有别于 以前的疫苗突发性和广泛性，受保护的RM在血浆中表现出病毒爆发 根据感染的大小不同，然后立即控制到无法检测的水平。保护性关联 在疫苗阶段产生的总的SIV特异性CD8+T细胞的程度，并在 绝大多数受保护的RM(16/17)为期12个月。这些数据表明了一种新的保护模式 与非常早期的控制一致，可能发生在病毒进入部位和/或病毒早期部位 复制和扩增，并涉及组织驻留的CD8+透射电子显微镜。值得注意的是，表位靶向 CMV载体的SIV特异性CD8+T细胞反应不同于传统病毒诱导的反应 载体或SIV本身，不包括内部处理的典型免疫优势表位和 由受病毒感染的细胞呈现。此差异表位靶向wt CMV载体诱导的CD8+T细胞 反应是由于CMV基因的活性，它抑制了I类MHC限制性的抗原提呈(US2-11 同源物)，因为US2-11缺失CMV/SIV载体诱导CD8+T细胞反应，包括显著的 对常规(“内部加工”)SIV表位的反应。在这个项目中，我们寻求1)改进 巨细胞病毒载体介导的保护作用及其优化(表位匹配)研究 CMV/SIV载体启动子的异源素数，2)确定US2-11是否缺失RhCMV/SIV载体， 将CMV/SIV载体重定向至典型(直接呈现)免疫显性的CD8+TEM型反应 3)决定复制缺陷和细胞趋向性修饰的有效性 CMV载体(分别在项目1和2中开发)和4)进一步定义了 巨细胞病毒载体所提供的独特保护作用可激发免疫应答。 相关性(请参阅说明)： 在世界范围内，2007年发生了约250万新的艾滋病毒感染(在一些地区的流行率 南部非洲超过15%)，人们普遍认为有效的预防性疫苗是唯一 控制艾滋病毒/艾滋病流行的实际手段。我们已经证明了 巨细胞病毒载体可利用组织驻留效应记忆T细胞对抗艾滋病 病毒在感染的早期，并能保护恒河猴免受黏膜后的进行性感染 挑战。本应用中提出的工作将增强CMV载体的安全性，优化其 并为这一新疫苗方法的进一步临床开发提供了关键信息。

Two nonhuman primate efficacy studies have convincingly demonstrated that wildtype (wt) CMV/SIV vectors can 1) re-infect CMV+ rhesus macaques (RM), 2) during re-infection, elicit potent and persistent SIV- specific CD4+ and CD8+ T cell responses with a strong "effector memory" (TEM) bias, and 3) completely protect ~50% of vaccinated RM from progressive SIV infecfion after limifing dose rectal challenge with the highly pathogenic, CCR5-tropic SIVmac239 virus. The protection manifested in these RM is distinct from previous vaccines in its abruptness and extent, with protected RM exhibiting a viral burst in plasma of varying size upon inifial infecfion, followed by immediate control to undetectable levels. Protecfion correlates with the extent of total SIV-specific CD8+ T cells generated during the vaccine phase, and is stable in the vast majority of protected RM (16/17) for >12 months. These data indicate a novel pattern of protection consistent with very early control, likely taking place at the site of viral entry and/or early sites of viral replication and amplificafion, and involving tissue-resident CD8+ TEM. Significantly, the epitope targeting of CMV-vectored, SIV-specific CD8+ T cell responses is distinct from responses elicited by conventional viral vectors or SIV itself, excluding the typical immunodominant epitopes that are internally processed in and presented by virally infected cells. This differential epitope targeting of wt CMV vector-elicited CD8+ T cell responses is due to the activity of CMV genes that inhibit class I MHC-restricted Ag presentation (US2-11 homologues), as US2-11 deletant CMV/SIV vectors elicit CD8+ T cell responses that include prominent responses to the conventional ("internally processed") SIV epitopes. In this project, we seek to 1) improve the efficacy of CMV vector mediated protection with development of an optimized (epitope "matched") heterologous prime for a CMV/SIV vector boost, 2) determine whether US2-11 deletant RhCMV/SIV vectors, which redirect CMV/SIV vector elicited CD8+ TEM responses to typical (directly presented) immunodominant epitopes, have increased efficacy, 3) determine the efficacy of replicafion-deficient and cell tropism-modified CMV vectors (developed in Projects 1 and 2, respectively), and 4) further define immunologic correlates of the unique protection afforded by CMV-vector elicited immune responses. RELEVANCE (See Instructions): Worldwide, ~2.5 million new HIV infections occurred in 2007 (with prevalence rates in some areas of southern Africa exceeding 15%), and it is generally agreed that an effective prophylacfic vaccine is the only practical means by which the HIV/AIDS epidemic can be controlled. We have demonstrated that cytomegalovirus (CMV) vectors can harness tissue resident effector memory T cells to combat the AIDS virus very early in infection, and can protect rhesus monkeys from progressive infection after mucosal challenge. The work proposed in this applicafion will enhance the safety of CMV vectors, optimize their efficacy, and provide crucial information for the further clinical development of this novel vaccine approach.