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（通过应用程序提供）：肠道菌群组成的改变是在包括慢性HIV感染在内的慢性炎症性非感染和传染病中发现的。这种变化可能影响宿主对病原体和疫苗的免疫调查。但是，我们对基线肠道微生物组对宿主免疫调查的影响对疫苗和病原体的影响有限。拟议的R01应用将利用艾滋病的非人类灵长类动物免疫缺陷病毒（SIV）模型来研究肠道微生物组对诱导宿主免疫调查的影响SIV疫苗和粘膜SIV攻击的影响。这项研究将利用加利福尼亚国家灵长类动物中心（CNPRC）的独特资源，其中包括特定的无病原体（SPF）和常规提高的（非SPF）恒河猕猴。我们的初步数据表明，SPF和非SPF猕猴显示出与表型和功能上不同T和B细胞子集相关的独特肠道微生物群落。 SPF动物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，通常对多种疱疹病毒呈阳性。 SPF和非SPF猕猴允许与慢性亚临床感染相关的微生物群的改变对影响的影响，引起了对SIV疫苗的免疫反应的改变。这种机会与了解具有不同水平的慢性病毒感染和潜在改变肠道微生物组的发展世界和发达国家的人群中疫苗反应的变异性高度相关。我们将利用一个 novel vaccine formula 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 efficiency in the context of distinct gut microbiota composition through the use of the unique SPF和非SPF队列。我们将检验以下假设：与许多人类种群典型的亚临床病毒感染相关的肠道微生物群可能会影响免疫调查的大小和多样性对SIV疫苗和疫苗效率。目标1：研究不同肠道微生物组组成和多样性对SIV疫苗诱导的SPF和非SPF恒河猕猴的免疫复杂的影响。恒河猕猴将通过一种新型的基于RHCMV-SIV的疫苗进行免疫，该疫苗包含TLR5调整，先天和病毒特异性的细胞和体液免疫调查，将在SPF和非SPF组之间进行比较。 AIM 2：研究肠道微生物组组成和多样性对免疫抑制中免疫抑制中SIV感染的宿主免疫调查的影响，在免疫抑制和天真，SPF和非SPF和非SPF恒河猴。拟议的研究具有潜力，可以提供有关了解基线微生物组组成和对HIV疫苗相关的免疫回应影响的影响，并有助于开发疗法的创新方法。