The Impact of Tolerance in the Newborn on Lentiviral Infection

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疾病的疫苗接种的新方法，即：创建一种疫苗，该疫苗将预防而不是引发针对该病毒的强大免疫反应。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保护艾滋病毒;另一方面，似乎很明显，艾滋病毒的复制和传播是由与免疫激活和炎症相关的前病毒作用促进的，而不是阻碍的。这些观察结果提示了另一种假设：对艾滋病毒的最佳反应可能是根本没有反应，即，一种有效的疫苗应该诱导对艾滋病毒的耐受性。对HIV的耐受性可能导致感染失败，因为缺乏通常驱动病毒复制和传播的炎症效应（例如，某些细胞因子的前病毒影响和细胞增殖和迁移速率的提高），感染的细胞可以简单地被清除。为了验证这一假设，我们建议在对慢病毒特异性耐受的宿主背景下研究慢病毒感染。考虑到我们在人胎儿中诱导耐受性方面的新发现，我们将依赖于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（子宫内注射抗原和出生时口服抗原）之一或其组合诱导耐受性。在每种情况下，我们假设抗原特异性耐受将被诱导，因为致耐受性胎儿T细胞谱系将应答。然后，我们将评估对SIV耐受的新生儿是否更能够（或更少）清除致病性SIV攻击。这些实验的数据将大大扩展我们对胎儿和新生儿耐受诱导的理解。我们将了解胎儿猕猴是否像胎儿人类一样，可以对外源性药物产生耐受性反应，包括Treg的主动抑制。我们也将首次能够探索非人灵长类新生儿口服耐受诱导的机制。当我们在致病性SIV攻击的背景下研究这些关于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HIV感染母亲所生的婴儿都没有感染;（B）如何创造一种有效的HIV疫苗，因为它诱导了致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有关，原因有二。首先，它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HIV的方法也可能被证明对其他慢性传染病的保护性疫苗接种有用（例如，结核病和疟疾），这些疾病通常与艾滋病毒共存，也可以对抗其他疾病（例如，自身免疫疾病）或病症（例如，器官移植），其中抗原特异性耐受的诱导可能是有益的。

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.