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

慢性病毒感染和微生物群改变对艾滋病毒疫苗功效的影响

• 批准号: 9078765
• 负责人: Peter A Barry
• 金额: $ 77.31万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-18 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9078765
• 关键词: AIDS Vaccines; Acquired Immunodeficiency Syndrome; Address; Adjuvant; Animals; Antibodies; B-Lymphocyte Subsets; California; Cercopithecine Herpesvirus 1; Chronic; Communicable Diseases; Cytomegalovirus; Data; Disease; Flagellin; Gagging; HIV Infections; HIV vaccine; HIV-1; Health; Herpesviridae; Human; Immune; Immune Cell Activation; Immune response; Immunization; Individual; Infection; Inflammatory; Investigation; Knowledge; Ligands; Macaca; Macaca mulatta; Mediating; Modeling; Oral; Population; Primates; Resources; Rhadinovirus; Role; SIV; Simian Foamy Virus; Specific Pathogen Frees; Stimulus; T-Lymphocyte; TLR5 gene; Testing; Type D Retrovirus; Vaccines; Viral Antigens; Virus; Virus Diseases; base; cohort; commensal microbes; cross reactivity; germ free condition; gut microbiota; immunogenicity; influenza virus vaccine; innovation; insight; microbial; microbial community; microbiome; nonhuman primate; novel; novel vaccines; pathogen; response; retanef; vaccine development; vaccine efficacy; vaccine response; vector

 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.

 描述（由申请人提供）：在慢性炎症性非感染性和感染性疾病（包括慢性HIV感染）中发现肠道微生物群组成的改变。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组对宿主对疫苗和病原体的免疫应答的影响，我们的知识有限。拟议的R 01申请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对诱导宿主对SIV疫苗和粘膜SIV攻击的免疫应答的影响。本研究将利用加州国家灵长类动物中心（CNPRC）的独特资源，包括无特定病原体（SPF）和常规饲养（非SPF）的恒河猴。我们的初步数据表明，SPF和非SPF猕猴显示出不同的肠道微生物群落，与表型和功能多样的T和B细胞亚群相关。SPF动物饲养时没有常见的慢性病毒感染。相比之下，非SPF动物自然暴露于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诱导的对SIV疫苗的免疫应答性改变的背景下。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变异性高度相关，这些人群具有不同程度的既存慢性病毒感染和潜在改变的肠道微生物组。我们将利用 基于表达SIV抗原的RhCMV载体（RhCMV-Gag、RhCMV-Retanef、RhCMV-Env）和表达与TLR 5配体融合的SIV抗原的RhCMV载体（RhCMV-SIV-Gag-FliC）的新型疫苗制剂，以通过使用独特的SPF和非SPF群组在不同的肠道微生物群组成的背景下确定疫苗免疫原性和功效。我们将检验以下假设，即与许多人群典型的亚临床病毒感染相关的肠道微生物群可能影响对SIV疫苗和疫苗效力的免疫应答的幅度和多样性。目标1：研究不同的肠道微生物组组成和多样性对SPF和非SPF恒河猴的SIV疫苗诱导的免疫应答的影响。将用含有TLR 5佐剂的新型RhCMV-SIV疫苗免疫恒河猴，并将在SPF和非SPF组之间比较先天性和病毒特异性细胞和体液免疫应答。目标二：研究肠道微生物组组成和多样性对免疫和幼稚、SPF和非SPF恒河猴中SIV感染的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HIV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。