Improved RhCMV/SIV vaccine efficacy via IL-10 pathway modulation

该项目的目标是测试基于恒河猴巨细胞病毒的SIV疫苗(RhCMV/SIV)是否可以 通过IL-10途径调节改善，获得明显超过50%的保护效果。我们发现 缺失病毒IL-10基因的第二代RhCMVdIL10/SIV疫苗保护非人灵长类动物 婴儿，而第一代(IL-10完整)RhCMV/SIV疫苗不能。第一代疫苗已经被 证明只对野生型RhCMV血清阳性的猕猴有效，这些猕猴对病毒IL-10有中和抗体。 这项工作的意义在于，如果成功，它将为(I)新的候选艾滋病毒疫苗提供更多的 在部分或所有人口部分中的有效性，(2)对以前的 RhCMV/SIV疫苗保护性的模糊模式，(Iii)控制IL-10的新药理工具 以及(Iv)对细胞和病毒IL-10途径调节后果的免疫学洞察。 我们的初步数据显示，感染野生型恒河猴巨细胞病毒(WtRhCMV)的恒河猴 对病毒白介素10(VIL-10)的免疫应答，这在大多数情况下会导致产生 中和抗体。RhCMV/SIV疫苗严格保护~50%的wtRhCMV+，但不能保护wtRhCMV- 血清阴性猴子抗SIV挑战。缺失病毒IL-10的第二代RhCMV/SIV疫苗 然而，基因可以保护血清阴性的猕猴。 我们假设在抑制宿主IL-10信号的情况下接种RhCMV/SIV将实现 对婴儿和成年猕猴的疗效卓越(&gt；50%)。我们的具体目标是： 目的1.确定IL-10升高或降低的转录和免疫学特征 使用先前收集的样本发送信号。在这里，我们确定了宿主的真实转录签名 使用接受抗IL-10抗体或强制表达IL-10的动物的样本发出IL-10信号。我们 然后在存在不同水平的病毒IL-10的情况下评估宿主对RhCMV/SIV疫苗的反应 中和以确定这种中和如何影响(I)宿主IL-10信号，(Ii)产生 与保护相关的转录签名，以及(Iii)疫苗效力。 目的2.检测细胞IL-10抑制是否能增强婴儿(RhCMV阴性)猕猴的疫苗效力。 由于病毒IL-10的缺失可能会干扰宿主的IL-10反应，我们进一步推断 干预(通过注射中和的抗IL-10抗体)将进一步增强疫苗效力。在这 目的我们单独或在中和抗CIL-10抗体存在的情况下给予RhCMVdIL10/SIVgag。 目的3.测试细胞和/或病毒抑制IL-10是否能增强成人疫苗的效力(RhCMV阳性) 猕猴。在这里，我们测试完全抑制病毒和/或细胞IL-10是否可以显著提高疗效。 综上所述，这些研究将对IL-10信号在RhCMV/SIV疫苗中的作用提供清晰的理解 并可能为85%-100%有效的新疫苗方案指明方向。

The goal of this project is to test if rhesus cytomegalovirus-based SIV vaccines (RhCMV/SIV) can be improved via IL-10 pathway modulation to obtain significantly over 50% protective efficacy. We found that second-generation RhCMVdIL10/SIV vaccines lacking the viral IL-10 gene protect non-human primate infants, while first-generation (IL-10 intact) RhCMV/SIV vaccines do not. First-generation vaccines have been proven effective only in wild-type RhCMV-seropositive macaques having neutralizing antibodies to viral IL-10. The significance of this work is that if successful it will provide (i) new candidate HIV vaccines with greater efficacy in some or all segments of the population, (ii) a coherent, mechanistic explanation for previously obscure patterns of RhCMV/SIV vaccine protectiveness, (iii) new pharmacologic tools for control over IL-10 signaling, and (iv) immunologic insight into consequences of cellular and viral IL-10 pathway modulation. Our preliminary data show that rhesus macaques infected by wild-type rhesus cytomegalovirus (wtRhCMV) mount immune responses to viral interleukin-10 (vIL-10), which in most cases leads to generation of neutralizing antibodies. RhCMV/SIV vaccine stringently protects ~50% of such wtRhCMV+ but not wtRhCMV- seronegative monkeys against SIV challenge. A second-generation RhCMV/SIV vaccine lacking the viral IL-10 gene, however, can protect seronegative macaques. We hypothesize that RhCMV/SIV vaccination in the context of inhibited host IL-10 signaling will achieve superior efficacy (>50%) in infant and adult macaques. Our specific aims are: Aim 1. Define the transcriptomic and immunologic signatures of increased or decreased IL-10 signaling using previously collected samples. Here we determine the true transcriptomic signature of host IL-10 signaling using samples from animals receiving anti-IL-10 antibody or with forced IL-10 expression. We then evaluate host responses to RhCMV/SIV vaccination in the presence of varying levels of viral IL-10 neutralization to determine how such neutralization affects (i) host IL-10 signaling, (ii) likelihood of generating a transcriptomic signature associated with protection, and (iii) vaccine efficacy. Aim 2. Test if cellular IL-10 inhibition augments vaccine efficacy in infant (RhCMV-negative) macaques. Since viral IL-10 deletion presumably interferes with the host IL-10 response, we reason that further interference (via administration of neutralizing anti-IL-10 antibody) will further augment vaccine efficacy. In this aim we therefore administer RhCMVdIL10/SIVgag alone or in the presence of neutralizing anti-cIL-10 antibody. Aim 3. Test if cellular and/or viral IL-10 inhibition augment vaccine efficacy in adult (RhCMV-positive) macaques. Here we test if complete inhibition of viral and/or cellular IL-10 can substantially increase efficacy. Together these studies will provide clear understanding of the role of IL-10 signaling in RhCMV/SIV vaccine efficacy and may point the way to new vaccine regimens that are 85-100% effective.