Alloimmunization as a novel prophylactic vaccine for AIDS viruses

 描述（由申请人提供）：人类免疫缺陷病毒（HIV）的变异性使得难以开发直接靶向病毒蛋白的有效疫苗。另一种策略是将免疫反应集中在从感染细胞出芽时并入病毒的多态性细胞蛋白上。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。早期在猕猴中进行的HIV疫苗研究观察到了对猴免疫缺陷病毒（SIV）感染的显著保护水平。然而，人们很快发现，关键成分是用于制备疫苗的人类蛋白质，而不是病毒抗原。这表明，掺入病毒包膜中的人类蛋白质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机会，以防止病毒传播。 主要组织相容性复合体（MHC）分子是病毒中主要的人类蛋白质之一。MHC分子在HIV病毒颗粒表面的丰度是病毒包膜蛋白的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。 同种异体反应性细胞免疫应答可能提供对抗病毒感染的重要第二道防线。用伴侣的细胞免疫的妇女显示T细胞产生的抗病毒因子增加，可以阻止艾滋病毒感染。这表明， 多态性细胞蛋白可以创造一个环境，其中CD4 + T细胞对HIV感染较不敏感。同种免疫的对照研究是困难的。在本提案中，我们 将利用猕猴（MCM）的独特遗传学来检验同种异体反应性免疫反应可以抑制SIV感染的假设。MCM仅具有少量表达的MHC分子，使得可以将确定的MHC分子掺入SIV病毒体中，特异性靶向针对确定的宿主分子的同种免疫应答，并表征SIV原液上的蛋白质。 我们将通过以下具体目标来检验这一假设： 目的1：评估同种异体反应性免疫应答保护MCM免受SIV感染的能力。我们将用来自表达不同MHC分子的其他MCM的细胞同种免疫MCM。同种免疫的MCM以及模拟接种和未接种对照将用在用于免疫的MCM细胞中生长的SIV进行粘膜攻击。 该提案将评估同种异体免疫应答对病毒体表面上的宿主多态性分子的预防潜力。如果成功，它将提供一个创新的， 这是一个实用、安全的策略，可以规避HIV病毒变异的挑战。

 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.