Enhancing RhCMV/SIV Vector Efficacy

两项非人灵长类动物疗效研究令人信服地证明，野生型（wt）CMV/SIV 载体可以1）再感染CMV+恒河猴（RM），2）在再感染期间，引发有效和持续的SIV-1， 特异性CD 4+和CD 8 + T细胞应答，具有强“效应记忆”（TEM）偏倚，和3）完全 在有限剂量直肠攻毒后，保护约50%接种疫苗的RM免受进行性SIV感染 高致病性嗜CCR 5 SIVmac 239病毒。这些RM中体现的保护与 先前的疫苗在其效力和程度上，受保护的RM在血浆中表现出病毒爆发， 在感染后改变大小，然后立即控制到不可检测的水平。保护相关 与疫苗阶段产生的总SIV特异性CD 8 + T细胞的程度相关，并且在 绝大多数受保护RM（16/17）>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的部位和/或病毒感染的早期部位。 复制和扩增，并涉及组织驻留的CD 8 + TEM。值得注意的是，表位靶向 CMV介导的SIV特异性CD 8 + T细胞应答与常规病毒介导的应答不同。 载体或SIV本身，不包括典型的免疫显性表位， 由病毒感染的细胞呈现。这种靶向野生型CMV载体的差异表位诱导了CD 8 + T细胞 应答是由于抑制I类MHC限制性Ag呈递的CMV基因的活性（US 2 -11 同源物），因为US 2 -11缺失CMV/SIV载体引发CD 8 + T细胞应答，包括显著的 对常规（“内部加工”）SIV表位的应答。在这个项目中，我们寻求1）改善 CMV载体介导的保护的功效与优化的（表位“匹配”） 异源引发CMV/SIV载体加强，2）确定US 2 -11缺失RhCMV/SIV载体， 其重定向CMV/SIV载体引起对典型的（直接呈递的）免疫显性的CD 8 + TEM应答， 表位，具有增加的功效，3）确定复制缺陷型和细胞向性修饰型的功效， CMV载体（分别在项目1和2中开发），和4）进一步定义了 CMV-载体提供的独特保护引起免疫应答。 相关性（见说明）： 2007年，全世界约有250万人新感染艾滋病毒（在某些地区的流行率为10%）。 南部非洲超过15%），普遍认为，有效的疫苗是唯一的 控制艾滋病毒/艾滋病流行病的实际手段。我们已经证明 巨细胞病毒（CMV）载体可以利用组织驻留效应记忆T细胞来对抗艾滋病 病毒感染的早期，并能保护恒河猴粘膜后进行性感染 挑战.在本申请中提出的工作将增强CMV载体的安全性，优化它们的生物学特性。 有效性，并为这种新型疫苗方法的进一步临床开发提供关键信息。

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.