GBV-C-mediated protection from AIDS in humans and GBV-C/SIV co-infected macaques

GBV-C介导的人类和GBV-C/SIV共感染猕猴免受艾滋病的保护

• 批准号: 9122300
• 负责人: David H. O'Connor
• 金额: $ 258.4万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-07 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9122300
• 关键词: AIDS therapy; Acquired Immunodeficiency Syndrome; Acute; Animal Model; Anti-Retroviral Agents; Attenuated; Blood; Blood specimen; Bone Marrow; Caring; Cells; Chronic; Clinical; Conflict (Psychology); Data; Disease; Epidemiologic Studies; Exhibits; GB virus C; HIV; HIV Infections; Human; Human Volunteers; Immune; Immunity; Immunology; In Vitro; Individual; Infection; Length; Leukocytes; Life; Lymphocyte Activation; Macaca; Measures; Mediating; Modeling; Monkeys; Mucous Membrane; Pan Genus; Papio; Pathogenesis; Pathology; Patients; Peripheral; Plasma; Qualifying; Quality of life; RNA; RNA Viruses; Recording of previous events; Research Personnel; SIV; Spleen; Testing; Therapeutic; Time; Tissues; Viremia; Virus; Virus Diseases; Virus Replication; Work; adaptive immunity; base; co-infection; experience; immune activation; improved; innovation; mortality; novel therapeutics; novel virus; protective effect; public health relevance; research study; virus pathogenesis

 DESCRIPTION (provided by applicant): GB virus C (GBV-C) is an enigmatic RNA virus. HIV+ people infected with GBV-C exhibit delayed progression to AIDS, a phenomenon we term "GBV-C mediated protection from AIDS (GPFA)." Though this protective effect has been substantiated by multiple studies, the mechanism of protection is unknown. There are at least three reasons why GPFA is understudied: (1) GBV-C grows poorly in vitro, (2) there is no animal model for exploring GPFA, and (3) human studies have focused almost entirely on cross-sectional sampling of blood, while we have now demonstrated that GBV-C RNA is much more abundant in other tissues, specifically the spleen and bone marrow. We developed an animal model to study GPFA by infecting macaques with GBV-C isolated from wild baboons. Importantly, we have shown that GBV-C infects both SIV+ and SIV-naive macaques and that macaque GBV-C infection recapitulates key features of human GBV-C infection: it causes high-titer, persistent viremia without any overt signs of disease. We have already used this model to demonstrate that GBV-C RNA is ~1,000x more abundant in spleen and bone marrow than blood. We hypothesize that GBV-C mediates protection from AIDS by directly interfering with lymphocyte activation, particularly in those tissues where GBV-C RNA is concentrated. To test this hypothesis, we will study GPFA in our pioneering model for GBV-C/SIV co-infection. Specifically, we will: Specific Aim 1: Determine the impact of GBV-C infection on peripheral immunity in the presence and absence of SIV co-infection. We will measure peripheral immune activation, virus-specific adaptive immunity, SIV-mediated immune pathology, and the effect of GBV-C on SIV pathogenesis during both acute and chronic infections. These experiments are essential for reconciling previous, conflicting observations about GPFA from studies of human blood. Specific Aim 2: Evaluate GBV-C-mediated immune activation in bone marrow, spleen, and gut mucosal tissues. We will compare immune activation between the bone marrow and blood from GBV-C±SIV-experimentally-infected macaques and GBV-C±HIV human volunteers. We will also characterize immune activation in the spleen and gut mucosa, two tissues where GBV-C and HIV/SIV, respectively, are concentrated. Understanding GPFA could have important practical implications. Aberrant immune activation is observed even in HIV+ patients treated with antiretrovirals; GBV-C might have therapeutic value if it interferes with immune activation. Furthermore, an estimated 7 million people eligible for ARV treatment remain untreated. GBV-C (or treatments that mimic its effects) could be a safe and simple healthspan extending treatment in settings where ARV access is low. This project is led by investigators experienced in HIV/SIV pathogenesis, novel virus characterization, and GBV-C immunology and pathogenesis. We are uniquely qualified to undertake this ambitious project.

 描述（由申请方提供）：GB病毒C（GBV-C）是一种神秘的RNA病毒。感染GBV-C的HIV+人群表现出延迟进展为AIDS，我们称这种现象为"GBV-C介导的艾滋病保护（GPFA）"。“虽然这种保护作用已被多项研究证实，但保护机制尚不清楚。至少有三个原因导致GPFA研究不足：（1）GBV-C在体外生长不良，（2）没有探索GPFA的动物模型，（3）人类研究几乎完全集中在血液的横截面采样上，而我们现在已经证明GBV-C RNA在其他组织中更丰富，特别是脾脏和骨髓。我们开发了一种动物模型，通过感染从野生狒狒分离的GBV-C来研究GPFA。重要的是，我们已经表明GBV-C感染SIV+和SIV-未感染猕猴，猕猴GBV-C感染重现了人GBV-C感染的关键特征：它引起高滴度，持续的病毒血症，没有任何明显的疾病体征。我们已经使用该模型证明GBV-C RNA在脾脏和骨髓中的丰度比血液高约1,000倍。我们推测GBV-C通过直接干扰淋巴细胞活化介导对艾滋病的保护，特别是在GBV-C RNA集中的那些组织中。为了验证这一假设，我们将在GBV-C/SIV合并感染的开创性模型中研究GPFA。具体而言，我们将：具体目标1：确定在存在和不存在SIV合并感染的情况下GBV-C感染对外周免疫的影响。我们将测量外周免疫激活，病毒特异性适应性免疫，SIV介导的免疫病理学，以及GBV-C在急性和慢性感染期间对SIV发病机制的影响。这些实验对于调和以前关于人类血液研究中GPFA的相互矛盾的观察结果至关重要。 具体目的2：评价骨髓、脾和肠粘膜组织中GBV-C介导的免疫活化。我们将比较GBV-C ± SIV实验感染猕猴和GBV-C ± HIV人类志愿者的骨髓和血液之间的免疫激活。我们还将表征脾和肠粘膜中的免疫激活，这两种组织分别集中了GBV-C和HIV/SIV。了解GPFA可能具有重要的实际意义。即使在接受抗逆转录病毒治疗的HIV+患者中也观察到异常的免疫激活;如果GBV-C干扰免疫激活，则可能具有治疗价值。此外，估计有700万有资格接受抗逆转录病毒治疗的人仍未得到治疗。GBV-C（或模拟其效果的治疗）可能是一种安全和简单的延长健康寿命的治疗方法，在ARV获得率较低的环境中。该项目由在HIV/SIV发病机制、新型病毒特征和GBV-C免疫学和发病机制方面经验丰富的研究人员领导。我们是唯一有资格承担这一雄心勃勃的项目。