CMV Vectors and Early Control of Mucosal SIV Challenge

CMV 载体和粘膜 SIV 挑战的早期控制

• 批准号: 8198144
• 负责人: Louis J. Picker
• 金额: $ 60万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-15 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8198144
• 关键词: AIDS Vaccines; AIDS/HIV problem; Adenovirus Vector; Area; Attenuated; Autopsy; CD4 Positive T Lymphocytes; CD8B1 gene; Cell physiology; Collaborations; Cytomegalovirus; Data; Detection; Development; Dose-Limiting; Epidemic; Exhibits; Frequencies; Goals; HIV; HIV Infections; Immune response; Infection; Intercept; Life; Macaca mulatta; Memory; Nested PCR; Nucleic Acids; Pattern; Phase; Plasma; Prevalence; SIV; SIV Vaccines; Site; Southern Africa; Systemic infection; T cell response; T memory cell; T-Lymphocyte; Time; Tissues; Vaccinated; Vaccine Research; Vaccines; Viral; Virus; Virus Diseases; Work; base; combat; nonhuman primate; novel; novel vaccines; poxvirus vectors; prophylactic; rectal; response; spatiotemporal; vaccine development; vector

We have demonstrated that 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" (T{EM}) bias, and 3) completely protect ~50% of vaccinated RM from progressive infection after limiting dose rectal challenge with the highly pathogenic 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 initial infection, followed by immediate control to undetectable levels. Although occasional viral blips in plasma are observed in protected RM, these decline with time, and after 1 year, protection is unaffected by CD8+ or CD4+ cell depletion, and extensive tissue analysis with ultrasensitive nested PCR has shown only rare detection of ~ single copy SIV nucleic acid and no viable SIV. Protection correlates with the total SIV-specific CD8+ T{EM} generated during the vaccine phase, and occurs without an anamnestic response. 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 amplification, and involving tissue-resident CD8+ T{EM-} Thus, CMV vectors and the "T{EM}" vaccine concept offer a new and powerful approach to HIV/AIDS vaccine development. In this project, our major goals are to delineate the mechanisms responsible for this unique protection, and determine the quantitative and/or qualitative determinants of protection vs. non-protection. First (S.A. 1), in collaboration with Project 1, we will use a serial necropsy approach to define the spatiotemporal progression of SIV infection after mucosal challenge of unvaccinated RM, both the trajectory of viral infection from the portal of entry to systemic infection, and the development of the anti-SIV immune response. Then (S.A. 2), with this baseline established, we will determine when and where the high frequency, tissue-based SIV-specific T cell responses elicited by RhCMV/SIV vectors intercept infection after mucosal challenge, delineate the function of these cells at this intercept, and determine the functional requirements for stringent viral control ~ in comparison to responses elicited by replication-deficient adenovirus and poxvirus vectors (Project 1) and live attenuated SIV vaccines (Project 3). Finally (S.A. 3), we will determine the extent of latent and/or active infection in short-term vs. long-term RhCMV/SIV vector protected RM and the activity of SIV-specific T cells in these RM, so as to determine the mechanism of long-term aviremic control, and to explore the possibility of eventual functional clearance of the infection.

我们已经证明 CMV/SIV 载体可以 1) 重新感染 CMV+ 恒河猴 (RM)，2) 再次感染，引发有效且持久的 SIV 特异性 CD4+ 和 CD8+ T 细胞反应，具有强大的“效应子” 记忆”(T{EM}) 偏差，以及 3) 完全保护约 50% 的接种 RM 在接种后免受进行性感染 用高致病性 SIVmac239 病毒进行限制剂量直肠攻击。保护体现在 这些 RM 的突然性和程度与以前的疫苗不同，受保护的 RM 表现出病毒性 初次感染后，会在不同大小的血浆中爆发，然后立即控制到不可检测的水平。 尽管在受保护的 RM 中偶尔观察到血浆中出现病毒斑点，但这些病毒斑点会随着时间的推移而下降，并且在 1 年，保护不受 CD8+ 或 CD4+ 细胞耗竭的影响，并且使用 超灵敏的巢式 PCR 表明仅罕见地检测到单拷贝 SIV 核酸，并且没有存活的 SIV。 保护作用与疫苗阶段产生的 SIV 特异性 CD8+ T{EM} 总量相关，并且发生 没有记忆反应。这些数据表明了一种与很早时期一致的新颖的保护模式 控制，可能发生在病毒进入位点和/或病毒复制和扩增的早期位点，以及 涉及组织驻留 CD8+ T{EM-} 因此，CMV 载体和“T{EM}”疫苗概念提供了一种新的、 艾滋病毒/艾滋病疫苗开发的有力方法。在这个项目中，我们的主要目标是描绘 负责这种独特保护的机制，并确定定量和/或定性 保护与不保护的决定因素。首先 (S.A. 1)，与项目 1 合作，我们将使用 连续尸检方法确定粘膜攻击后 SIV 感染的时空进展 未接种疫苗的 RM 的病毒感染从入口到全身感染的轨迹，以及 抗SIV免疫反应的发展。然后（S.A. 2），建立了这个基线，我们将 确定何时何地引发高频、基于组织的 SIV 特异性 T 细胞反应 RhCMV/SIV 载体在粘膜攻击后拦截感染，描述这些细胞在此的功能 拦截并确定严格病毒控制的功能要求 ~ 与响应进行比较 由复制缺陷型腺病毒和痘病毒载体（项目 1）以及减毒活 SIV 疫苗引发 （项目3）。最后（S.A. 3），我们将确定短期与长期潜伏和/或活动感染的程度。 长期的RhCMV/SIV载体保护了RM以及这些RM中SIV特异性T细胞的活性，从而 确定长期无病毒血症控制的机制，并探索最终功能性的可能性 清除感染。