Effect of host immunity stimulated by viral IL-10-deleted RhCMV vaccines on SIV rebound

病毒 IL-10 缺失的 RhCMV 疫苗刺激宿主免疫对 SIV 反弹的影响

• 批准号: 10205969
• 负责人: DENNIS J. HARTIGAN-O'CONNOR
• 金额: $ 78.25万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-19 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10205969
• 关键词: Affect; Anatomy; Animal Model; Animals; Autopsy; B-Lymphocytes; Biological Assay; Biological Markers; Blood; CD8-Positive T-Lymphocytes; Cells; Characteristics; Colon; Cytomegalovirus; Data; Development; Epigenetic Process; Exhibits; Frequencies; HIV; Human; Immune response; Immunity; Immunologics; Individual; Infection; Interferon Type II; Interleukin-10; Interruption; Kinetics; Location; Macaca; Macaca mulatta; Memory; Modeling; Natural Killer Cells; Patients; Peptides; Peripheral; Resistance; Role; SIV; SIV Vaccines; Sampling; Signal Transduction; T cell response; T memory cell; T-Lymphocyte; Testing; Tissue Sample; Tissues; Tropism; Vaccinated; Vaccination; Vaccine Therapy; Vaccines; Viral; Viral Load result; Viral reservoir; Virus; Withdrawal; acute infection; antiretroviral therapy; chronic infection; co-infection; cohort; digital; epigenetic regulation; lymph nodes; macrophage; memory CD4 T lymphocyte; preservation; response; seropositive; therapeutic evaluation; transcriptomics; vector; viral DNA

HIV rebound after interruption of anti-retroviral therapy (ART) is generally thought to reflect the size of the persistent reservoir found in long-lived memory CD4+ T cells, with a smaller reservoir reflected in delayed rebound. However, tissue reservoirs under ART suppression have been poorly characterized, so we do not know if characteristics of those reservoirs have a dominant impact on rebound kinetics. The contribution of host immune responses to rebound kinetics is also poorly understood, especially since most available data are focused on IFN-γ producing T cell responses that are not related to control of viral load in acute or chronic infection. It would be surprising if the indiscriminate total of such responses had an important impact on rebound. Project 2 will leverage unique advantages of the rhesus macaque model to understand how tissue reservoirs and host immunity impact rebound. The animal model will provide frequent longitudinal samples of tissue-resident cells and recrudescent virus throughout suppressive ART and during rebound, which will be characterized by Dr. Mario Stevenson under the auspices of Project 3. In addition, we have the unique capability in rhesus macaques to induce both Mamu-E-restricted CD8+ T cells and memory NK cells using viral IL-10-deleted RhCMV/SIV vaccines. In contrast to conventional class Ia-restricted CD8+ T cells expressing IFN-γ,1,2 Mamu-E-restricted CD8+ T cells likely contribute to suppression and even elimination of virus soon after infection, when SIV is replicating quickly in T cells, many of which are confined to gut tissue. We propose that the situation in a human patient after ART withdrawal is similar to that early stage of infection, in that HIV rebound presumably begins from a small number of cells reactivating virus in restricted anatomic sites. Thus, if HLA-E-restricted responses are present in some human patients (Project 1) or can be induced in vaccinated humans or macaques, these individuals might exhibit delayed rebound. We hypothesize that the unique immune responses elicited by RhCMV/SIV therapeutic vaccination under ART, but not conventional CTL elicited by Ad/SIV vaccine when used alone, alter both tissue viral reservoirs and SIV rebound kinetics. Our specific aims are: 1. Test if therapeutic RhCMV/SIV vaccination is superior to Ad/SIV vaccination for depletion of the Tfh-resident SIV reservoir. 2. Test if RhCMV/SIV vaccination slows rebound kinetics. 3. Determine if HLA/Mamu-E-restricted T cell responses are induced in unvaccinated individuals by CMV co-infection and are a biomarker for delayed rebound.

抗逆转录病毒治疗（ART）中断后的艾滋病毒反弹通常被认为反映了艾滋病毒感染的规模。 在长寿命记忆CD 4 + T细胞中发现了持久的储库，在延迟记忆中反映了较小的储库。 反弹然而，ART抑制下的组织储库的特征很差，所以我们不 知道这些储层的特性是否对回弹动力学具有主要影响。的贡献 宿主对反弹动力学的免疫反应也知之甚少，特别是因为大多数可用数据都是 关注产生IFN-γ的T细胞应答，其与急性或慢性病毒感染中的病毒载量控制无关。 感染如果这种不加区别的反应总数对下列问题产生了重要影响，那将是令人惊讶的。 反弹 项目2将利用恒河猴模型的独特优势来了解组织如何 水库和宿主免疫力的影响反弹。动物模型将提供频繁的纵向样本 组织驻留细胞和复发病毒在整个抑制性ART和反弹期间，这将是 由马里奥史蒂文森博士在项目3的主持下进行表征。此外，我们还拥有独特的 在恒河猴中使用病毒诱导Mamu-E限制性CD 8 + T细胞和记忆NK细胞的能力 IL-10缺失的RhCMV/SIV疫苗。与表达Ia类限制性CD 8 + T细胞相比， IFN-γ、1，2 Mamu-E限制性CD 8 + T细胞可能有助于抑制甚至很快消除病毒 感染后，SIV在T细胞中快速复制，其中许多局限于肠道组织。我们提出 人类患者在停止抗逆转录病毒治疗后的情况与感染的早期阶段相似， 反弹大概开始于少量细胞在有限的解剖部位重新激活病毒。因此，在本发明中， 如果HLA-E限制性应答存在于某些人类患者中（项目1）或可在接种疫苗的人中诱导， 人类或猕猴，这些个体可能表现出延迟反弹。 我们假设在ART下由RhCMV/SIV治疗性疫苗接种引起的独特免疫应答， 而不是由Ad/SIV疫苗单独使用时引发的常规CTL，改变组织病毒储库和SIV 回弹动力学我们的具体目标是：1.检测治疗性RhCMV/SIV疫苗接种是否优于Ad/SIV上级 接种疫苗以耗尽Tfh驻留的SIV储库。2.检测RhCMV/SIV疫苗接种是否减缓反弹 动力学。3.确定HLA/Mamu-E限制性T细胞应答是否在未接种疫苗的个体中诱导， CMV合并感染是延迟反弹的生物标志物。