Impact of chronic viral infections and altered microbiota on HIV vaccine efficacy

 描述(申请人提供)：慢性炎症性、非感染性和感染性疾病，包括慢性HIV感染，均可发现肠道微生物区系的改变。这种变化可能会影响宿主对病原体和疫苗的免疫反应。然而，关于基线肠道微生物群对宿主对疫苗和病原体的免疫反应的影响，我们的了解有限。建议的R01应用程序将利用艾滋病的非人灵长类猴免疫缺陷病毒(SIV)模型来研究肠道微生物组在诱导宿主对SIV疫苗和粘膜SIV攻击的免疫反应中的影响。这项研究将利用加州国家灵长类中心(CNPRC)的独特资源，其中包括无特定病原体(SPF)和常规饲养(非SPF)的恒河猴。我们的初步数据显示，SPF猕猴和非SPF猕猴表现出不同的肠道微生物群落，这些微生物群落与表型和功能多样化的T和B细胞亚群相关。SPF动物是在没有常见的慢性病毒感染的情况下长大的。相比之下，非SPF动物自然暴露于来自其他动物的慢性病毒感染，并且通常对多种疱疹病毒呈阳性。SPF和非SPF猕猴队列允许研究与慢性亚临床感染相关的改变的微生物群的影响，以及在慢性亚临床感染导致对SIV疫苗的免疫反应性改变的背景下。这一机会与了解来自发展中国家和发达国家的人群中疫苗反应的可变性高度相关，这些发展中国家和发达国家先前存在不同程度的慢性病毒感染，并可能改变肠道微生物群。我们将利用一个 基于表达SIV抗原的RhCMV载体(RhCMV-Gag、RhCMV-Retanef、RhCMV-Env)和表达SIV抗原与TLR5配体融合的RhCMV载体(RhCMV-SIV-Gag-Flic)的新型疫苗配方，通过使用独特的SPF和非SPF队列，在不同的肠道微生物群组成的背景下确定疫苗的免疫原性和有效性。我们将测试这一假设，即与许多人类群体典型的亚临床病毒感染相关的肠道微生物区系可能会影响对SIV疫苗的免疫反应的幅度和多样性以及疫苗的效力。目的1：研究不同肠道微生物群组成和多样性对SIV疫苗诱导SPF和Non-SPF猕猴免疫应答的影响。将用一种新型的基于RhCMV-SIV的疫苗免疫恒河猴，该疫苗含有TLR5佐剂和天然和病毒特异性细胞和体液免疫反应，将在SPF组和非SPF组之间进行比较。目的：研究免疫恒河猴、SPF恒河猴和非SPF恒河猴肠道微生物群落组成和多样性对SIV感染宿主免疫应答的影响。这项拟议的研究有可能为了解基线微生物组组成和相关免疫细胞激活状态对宿主对艾滋病毒疫苗和病毒的免疫反应的影响提供见解，并有助于开发创新的治疗方法。

 DESCRIPTION (provided by applicant): Alterations in gut microbiota composition are found in chronic inflammatory non-infectious and infectious diseases including chronic HIV infection. Such changes may influence host immune responses to pathogens and vaccines. However, our knowledge is limited regarding the influence of the baseline gut microbiome on the host immune responses to vaccines and pathogens. The proposed R01 application will utilize the nonhuman primate simian immunodeficiency virus (SIV) model of AIDS to investigate the influence of the gut microbiome on the induction of host immune responses to a SIV vaccine and to mucosal SIV challenge. This study will capitalize on the unique resource at the California National Primate Center (CNPRC) that includes specific pathogen free (SPF) and conventionally raised (non-SPF) rhesus macaques. Our preliminary data show that SPF and non-SPF macaques show distinct gut microbial communities that correlate with phenotypically and functionally diverse T and B cell subsets. SPF animals are raised free of commonly found chronic viral infections. In contrast, non-SPF animals are naturally exposed to chronic viral infections from other animals and are typically positive for multiple herpes viruses. SPF and non-SPF macaque cohorts permit investigation of the influence by altered microbiota associated with, and in the context of chronic subclinical infection induced alterations of immune responsiveness to SIV vaccines. This opportunity is highly relevant to understanding the variability in vaccine responses among populations from developing and developed worlds that have different levels of pre-existing chronic viral infections and potentially altered gut microbiomes. We will utilize a novel vaccine formulation based on RhCMV vectors expressing SIV antigens (RhCMV-Gag, RhCMV-Retanef, RhCMV-Env) and an RhCMV vector expressing an SIV antigen fused to a TLR5 ligand (RhCMV-SIV-Gag-FliC) to determine vaccine immunogenicity and efficacy in the context of distinct gut microbiota composition through the use of the unique SPF and non-SPF cohorts. We will test the hypothesis that gut microbiota associated with subclinical viral infections typical to many human populations may impact the magnitude and diversity of the immune responses to a SIV vaccine and vaccine efficacy. Aim 1: Investigate the impact of distinct gut microbiome composition and diversity on the SIV vaccine-induced immune responses of SPF and non-SPF rhesus macaques. Rhesus macaques will be immunized with a novel RhCMV-SIV-based vaccine that contains a TLR5 adjuvant and innate and virus-specific cellular and humoral immune responses will be compared between SPF and non-SPF groups. Aim 2: Investigate the impact of the gut microbiome composition and diversity on the host immune responses to SIV infection in immunized and naive, SPF and non-SPF rhesus macaques. The proposed study has potential to provide insights into understanding the influence of baseline microbiome composition and associated immune cell activation status on the host immune responses to HIV vaccines and the virus and help develop innovative approaches to therapies.