The Impact of Tolerance in the Newborn on Lentiviral Infection

描述(由申请人提供)： 这项提议的实验解决了一种预防艾滋病毒疾病疫苗的新方法，即：创造一种将预防而不是引发对病毒的强大免疫反应的疫苗。这一方法的理由是几个观察结果：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具有保护作用；另一方面，似乎很明显，艾滋病毒的复制和传播受到与免疫激活和炎症相关的亲病毒效应的促进，而不是阻碍。这些观察结果引发了另一种假设：对艾滋病毒的最佳反应可能是完全没有反应，即有效的疫苗应该反而会诱导对艾滋病毒的耐受性。对艾滋病毒的耐受性可能导致流产感染，因为如果没有正常情况下推动病毒复制和传播的炎症的影响(例如，某些细胞因子的前病毒影响以及细胞增殖和迁移速度的增加)，受感染的细胞可能会被简单地清除。为了验证这一假设，我们建议在宿主对慢病毒具有特定耐受性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的新发现，我们将依靠一个特征良好的实验模型(恒河猴的SIV感染)通过两种已证实的途径之一(宫内注射抗原和出生时口服抗原)或通过两者的组合来诱导耐受。在每种情况下，我们假设抗原特异性耐受将被诱导，因为耐受性胎儿T细胞谱系将会有反应。然后，我们将评估对SIV耐受的新生儿是否更有(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。我们将了解胎儿猕猴是否像胎儿人类一样，对外源性物质产生耐受性反应，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服耐受诱导的机制。然后在致病性SIV挑战的背景下研究关于耐受诱导的基本知识时，我们还可能了解：(A)为什么艾滋病毒感染母亲所生的绝大多数婴儿没有感染，以及(B)如何创造有效的艾滋病毒疫苗，因为它诱导耐受性而不是免疫刺激性抗病毒反应。这些实验与公共健康有关，原因有两个。首先，他们可能会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，这里针对艾滋病毒使用的方法也可能被证明有助于预防经常与艾滋病毒共存的其他慢性传染病(例如结核病和疟疾)，以及预防其他疾病(例如自身免疫性疾病)或诱导抗原特异性耐受可能有益的情况(例如器官移植)。

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.