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: 8922481
• 负责人: David H. O'Connor
• 金额: $ 66.59万
• 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/8922481
• 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(申请人提供)：GB病毒C(GBV-C)是一种神秘的RNA病毒。感染GBV-C的HIV+患者表现出向艾滋病发展的延迟，我们将这种现象称为“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，但其保护机制尚不清楚。GPFA研究不足至少有三个原因：(1)GBV-C在体外生长不佳，(2)还没有探索GPFA的动物模型，(3)人类研究几乎完全集中在血液的横断面采样上，而我们现在已经证明GBV-C RNA在其他组织中更丰富，特别是脾和骨髓。我们建立了一种动物模型来研究GPFA，方法是用从野生狒狒中分离出的GBV-C感染猕猴。重要的是，我们已经证明了GBV-C感染SIV+和SIV-幼稚猕猴，并且猕猴GBV-C感染概括了人类GBV-C感染的主要特征：它导致高滴度、持续性的病毒血症，而没有任何明显的疾病迹象。我们已经使用这个模型证明了GBV-C RNA在脾和骨髓中的丰度是血液的1000倍。我们推测，GBV-C通过直接干扰淋巴细胞激活，特别是在GBV-C RNA集中的组织中，介导对艾滋病的保护。为了验证这一假设，我们将在我们的GBV-C/SIV联合感染的开创性模型中研究GPFA。具体地说，我们将：具体目标1：在存在和不存在SIV混合感染的情况下，确定GBV-C感染对外周免疫的影响。我们将在急性和慢性感染期间检测外周免疫激活、病毒特异性适应性免疫、SIV介导的免疫病理以及GBV-C在SIV发病机制中的作用。这些实验对于调和之前关于人体血液研究中关于GPFA的相互矛盾的观察是必不可少的。特定目的2：评价GBV-C在骨髓、脾和肠粘膜组织中的免疫激活作用。我们将比较实验感染GBV-C±SIV的猕猴和GBV-C±HIV人类志愿者的骨髓和血液的免疫活性。我们还将描述脾和肠粘膜中的免疫激活情况，这两种组织分别是GBV-C和HIV/SIV的集中地。理解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，它可能具有治疗价值。此外，估计有700万有资格接受抗逆转录病毒治疗的人仍未接受治疗。GBV-C(或模拟其效果的治疗)可能是一种安全和简单的健康范围，在抗逆转录病毒药物获得率较低的环境中延长治疗范围。该项目由在HIV/SIV发病机制、新型病毒特征以及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的公司。