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）： 该提案的实验介绍了一种针对HIV疾病的新方法，即：创建一种疫苗，可以防止而不是引起对病毒的强烈免疫反应。这种方法的基本原理是由几个观察结果引起的：一方面，没有明确的证据表明强大的免疫反应将对艾滋病毒有保护。另一方面，很明显，与免疫激活和炎症相关的促病毒作用促进而不是阻碍HIV复制和扩散。这些观察结果提出了一个替代假设：对HIV的最佳反应可能根本没有反应，即有效的疫苗应诱导对HIV的耐受性。对艾滋病毒的耐受性可能导致流产感染，因为没有炎症的影响通常会驱动病毒复制和扩散（例如，某些细胞因子的预期影响以及细胞增殖和迁移的增强速率）可以简单地清除感染细胞。为了检验这一假设，我们建议在对慢病毒特别耐受性的宿主中研究慢病毒感染。鉴于我们已经对人类胎儿的耐受性的诱导做出了新的发现，我们将依靠特征良好的实验模型（SIV感染恒河猴的SIV感染）来诱导通过两种经过验证的途径之一（子宫内注射抗原和出生时口服抗原的抗原）之一或结合的组合。在每种情况下，我们都会假设抗原特异性耐受性将被诱导，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宽容的新生儿是否能够（或更少）能够清除病原SIV挑战。这些实验的数据将大大扩展我们对胎儿和新生儿耐受性诱导的理解。我们将了解胎儿猕猴（例如胎儿人类）是否可以对包括Treg主动抑制的外源性剂产生耐受性反应。我们还将首次能够探索非人类灵长类动物新生儿口服耐受性的机制。当随后对耐受性诱导的这种基本知识在致病性SIV挑战的背景下进行研究时，我们还可以学习：（a）为什么艾滋病毒感染的母亲出生的绝大多数婴儿幸免于感染，以及（b）如何对HIV产生疫苗，这是有效的，因为它会引起耐受性抗药性反应，因为它会引起免疫抗毒素的反应。这些实验与公共卫生有关，原因有两个。首先，他们可以提供概念证明数据，以制定针对艾滋病毒的全新疫苗方法。 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.