Alloimmunization as a novel prophylactic vaccine for AIDS viruses

 描述(申请人提供)：人类免疫缺陷病毒(HIV)的变异性使开发直接针对病毒蛋白的有效疫苗变得困难。另一种策略是，当病毒从受感染的细胞中发芽时，将免疫反应集中在针对整合到病毒中的多态细胞蛋白上。来自同一物种成员的细胞蛋白的免疫识别被称为同种免疫。在猕猴身上进行的早期艾滋病毒疫苗研究发现，对猴免疫缺陷病毒(SIV)感染具有令人印象深刻的保护水平。然而，人们很快发现，关键成分是用于制备疫苗的人类蛋白，而不是病毒抗原。这表明，病毒包膜中的人类蛋白可能是艾滋病病毒的致命弱点，并为疫苗诱导的同种免疫反应提供了防止病毒传播的机会。 进入病毒的主要人类蛋白之一是主要组织相容性复合体(MHC)分子。HIV病毒颗粒表面的MHC分子比病毒包膜蛋白丰富10倍，这表明病毒上有足够的靶点供抗MHC抗体结合并发挥抗病毒作用。 同种异体细胞免疫反应可能为抵御病毒感染提供重要的第二道防线。用伴侣的细胞免疫的女性表现出T细胞产生的抗病毒因子增加，这种T细胞可以阻止艾滋病毒感染。这表明，使用 多态的细胞蛋白可能会创造一种环境，在这种环境中，CD4+T细胞不太容易受到艾滋病毒感染。同种异体免疫的对照研究是困难的。在这份提案中，我们 将利用毛里求斯食蟹猴(MCM)的独特遗传学来测试同种免疫反应可以抑制SIV感染的假设。MCM只有少量表达的MHC分子，这使得有可能将定义的MHC分子整合到SIV病毒粒子中，针对定义的宿主分子特异性地靶向同种免疫反应，并表征SIV库存上的蛋白质。 我们将通过以下具体目标来检验这一假设： 目的：评价同种异体免疫反应保护MCM免受SIV感染的能力。我们将用表达不同MHC分子的其他MCM的细胞对MCM进行同种免疫。同种免疫的MCM以及模拟接种和未接种的对照，将用在用于免疫的MCM细胞中生长的SIV进行粘膜攻击。 这项建议将评估针对病毒粒子表面宿主多态分子的同种异体免疫反应的预防潜力。如果成功，它将提供一种创新的、 规避艾滋病毒变异挑战的实用、安全的战略。

 DESCRIPTION (provided by applicant): The variability of human immunodeficiency virus (HIV) makes it difficult to develop effective vaccines directly targeting viral proteins. An alternative strategy is to focus immune responses against polymorphic cellular proteins incorporated into viruses as they bud from infected cells. Immune recognition of cellular proteins derived from members of the same species is referred to as alloimmunity. Early HIV vaccine studies in macaques observed impressive levels of protection from simian immunodeficiency virus (SIV) infection. It was quickly discovered, though, that the key components were human proteins used to prepare the vaccines rather than the viral antigens. This suggests that human proteins incorporated into the viral envelope may present an Achilles heel for AIDS viruses and provide an opportunity for vaccine-induced alloimmune responses to prevent virus transmission. One of the primary human proteins incorporated into the virus are major histocompatibility complex (MHC) molecules. MHC molecules are 10X more abundant on the surface of HIV virus particles than viral envelope proteins, suggesting that there are ample targets on the virus for anti-MHC antibodies to bind and exert an antiviral effect. Alloreactive cellular immune responses may provide an important second line of defense against viral infection. Women immunized with their partners' cells display increased production of antiviral factors by T cells that can block HIV infection. This indicates that immunization with polymorphic cellular proteins may create an environment where CD4+ T cells are less susceptible to HIV infection. Controlled studies of alloimmunity are difficult. In this proposal we will leverage the unique genetics of Mauritian cynomolgus macaques (MCM) to test the hypothesis that alloreactive immune responses can inhibit the acquisition of SIV infection. MCM have only a small number of expressed MHC molecules making it possible to incorporate defined MHC molecules in the SIV virions, specifically target alloimmune responses against defined host molecules, and characterize proteins on the SIV stock. We will test this hypothesis with the following Specific Aim: AIM1: Assess the ability of alloreactive immune responses to protect MCM from SIV infection. We will alloimmunize MCM with cells from other MCM that express distinct MHC molecules. The alloimmunized MCM, along with mock vaccinated and unvaccinated controls, will be mucosally challenged with SIV grown in the cells of the MCM used for immunization. This proposal will assess the prophylactic potential of allogeneic immune responses against host polymorphic molecules on the surface of virions. If successful, it will provide an innovative, practical, and safe strategy for circumventing the challenge of HIV viral variation.