The Impact of Tolerance in the Newborn on Lentiviral Infection

新生儿耐受性对慢病毒感染的影响

• 批准号: 8501944
• 负责人: JOSEPH M MCCUNE
• 金额: $ 0.28万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-12 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8501944
• 关键词: Accounting; Acute; Address; Alloantigen; Antigens; Antiviral Response; Autoimmune Diseases; B-Lymphocytes; Birth; Blood Circulation; CD3 Antigens; CD8B1 gene; Cell Lineage; Cell Proliferation; Cells; Chronic; Communicable Diseases; Data; Disease; Drug Formulations; Experimental Models; Fetus; Fostering; Gagging; HIV-1; Human; Immune; Immune response; Infection; Infection prevention; Inflammation; Injection of therapeutic agent; Knowledge; Learning; Lymphoid; Macaca; Macaca mulatta; Malaria; Mechanics; Mothers; Newborn Infant; Oral Administration; Organ; Organ Transplantation; Participant; Placenta; Pregnancy; Property; Public Health; Regulatory T-Lymphocyte; Route; SIV; Subfamily lentivirinae; T cell response; T-Lymphocyte; Testing; Time; Tuberculosis; Vaccination; Vaccines; Viral; Viral Load result; Virus; Virus Diseases; Virus Replication; Work; cell motility; cytokine; design; fetal; immune activation; immunogenic; in utero; nonhuman primate; novel strategies; oral tolerance; prevent; research study; response; vaccine candidate

DESCRIPTION (provided by applicant): The experiments of this proposal address a novel approach towards vaccination against HIV disease, namely: to create a vaccine that will prevent, rather than to elicit, a robust immune response against the virus. The rationale for this approach is prompted by several observations: on the one hand, there is no clear evidence that a robust immune response will be protective against HIV; on the other hand, it seems clear that HIV replication and spread are fostered, not hindered, by pro-viral effects associated with immune activation and inflammation. These observations prompt an alternative hypothesis: the best response to HIV might be no response at all, i.e., an effective vaccine should induce tolerance to HIV instead. Tolerance to HIV may result in abortive infection because, absent the effects of inflammation that normally drive viral replication and spread (e.g., the proviral impact of certain cytokines and of enhanced rates of cell proliferation and migration), infected cells may simply be cleared. To test this hypothesis, we propose to study lentiviral infection in the context of hosts made specifically tolerant to lentivirus. Given new findings that we have made about the induction of tolerance in the human fetus, we will rely upon a well-characterized experimental model (SIV infection of the rhesus macaque) to induce tolerance by one of two proven routes (injection of antigen in utero and oral administration of antigen at birth) or by a combination thereof. In each case, we postulate that antigen- specific tolerance will be induced because a tolerogenic fetal T cell lineage will respond. We will then assess whether newborns rendered tolerant to SIV are more (or less) able to clear a pathogenic SIV challenge. Data from these experiments will greatly expand our understanding of tolerance induction in the fetus and the newborn. We will learn whether the fetal macaque, like the fetal human, can mount a tolerogenic response against exogenous agents that includes active suppression by Treg. We will also, for the first time, be able to explore the mechanics of oral tolerance induction in the nonhuman primate newborn. When this basic knowledge about tolerance induction is then studied in the context of pathogenic SIV challenge, we might also learn: (a) why the overwhelming majority of babies born to HIV-infected mothers are spared infection and (b) how to create a vaccine against HIV that is effective because it induces a tolerogenic as opposed to an immunostimulatory antiviral response. These experiments are relevant to public health for two reasons. First, they may provide proof-of- concept data for the formulation of an entirely new type of vaccine approach against HIV. Secondly, the approach used here for HIV might also prove useful for protective vaccination against other chronic infectious diseases (e.g., tuberculosis and malaria) that often co-exist with HIV as well as against other illnesses (e.g., autoimmune diseases) or conditions (e.g., organ transplantation) in which the induction of antigen-specific tolerance might be beneficial.

描述（由申请人提供）： 该提案的实验提出了一种针对艾滋病毒疫苗接种的新方法，即：创造一种能够预防而不是引发针对该病毒的强大免疫反应的疫苗。这种方法的基本原理是由几个观察结果推动的：一方面，没有明确的证据表明强大的免疫反应可以预防艾滋病毒；另一方面，很明显，与免疫激活和炎症相关的促病毒作用会促进而不是阻碍艾滋病毒的复制和传播。这些观察结果提出了另一种假设：对艾滋病毒的最佳反应可能是根本没有反应，即有效的疫苗应该诱导对艾滋病毒的耐受性。对 HIV 的耐受可能会导致感染流产，因为如果没有通常驱动病毒复制和传播的炎症影响（例如某些细胞因子的前病毒影响以及细胞增殖和迁移率提高），受感染的细胞可能会被简单地清除。为了检验这一假设，我们建议在对慢病毒特异耐受的宿主的背景下研究慢病毒感染。鉴于我们在人类胎儿中诱导耐受性方面取得的新发现，我们将依靠一个充分表征的实验模型（恒河猴的 SIV 感染），通过两种已证实的途径之一（在子宫内注射抗原）诱导耐受性。和出生时口服抗原）或其组合。在每种情况下，我们假设都会诱导抗原特异性耐受，因为耐受性胎儿 T 细胞谱系会做出反应。然后，我们将评估对 SIV 具有耐受性的新生儿是否更有（或更少）能够清除致病性 SIV 挑战。这些实验的数据将极大地扩展我们对胎儿和新生儿耐受诱导的理解。我们将了解猕猴胎儿是否像人类胎儿一样，能够对外源性物质产生耐受反应，包括 Treg 的主动抑制。我们还将首次能够探索非人类灵长类新生儿口腔耐受诱导的机制。当在致病性 SIV 挑战的背景下研究有关耐受诱导的基本知识时，我们还可能了解到：(a) 为什么绝大多数艾滋病毒感染母亲所生的婴儿都没有受到感染，以及 (b) 如何研制疫苗对抗艾滋病毒是有效的，因为它诱导耐受性而不是免疫刺激性抗病毒反应。这些实验与公共卫生相关有两个原因。首先，他们可以为制定一种全新的艾滋病毒疫苗方法提供概念验证数据。其次，这里用于艾滋病毒的方法也可能被证明可用于针对通常与艾滋病毒共存的其他慢性传染病（例如结核病和疟疾）以及其他疾病（例如自身免疫性疾病）或病症（例如艾滋病毒）的保护性疫苗接种。 、器官移植），其中诱导抗原特异性耐受可能是有益的。