The effects of morphine on the immune responses against HIV in vivo

描述（由申请人提供）：药物滥用除了是艾滋病毒感染的危险因素外，还会对控制艾滋病毒复制所需的免疫反应产生深远影响。例如，CD8+ T细胞介导的免疫对抑制HIV的生产性感染至关重要，但吗啡严重阻碍了这种免疫。本研究旨在为吗啡调节CD4+ T细胞活化和分化的机制研究奠定基础。CD4+ T细胞分化为Th1谱系以及随后HIV特异性CD8+ T细胞的激活和分化是成功接种HIV疫苗所必需的。因此，实现我们的目标将使我们能够更好地了解阿片类药物如何损害艾滋病毒疫苗的效力。这种理解将使我们能够更好地为艾滋病毒疫苗的潜在接受者提供咨询。我们假设吗啡在初始CD4+ T细胞内诱导永久性变化，这样，在抗原刺激下，细胞被“预先编程”分化为Th2谱系。这一假设是基于我们对恒河猴的研究，恒河猴接受了吗啡治疗并感染了SIV。这些猴子无法产生CD8+ T细胞介导的免疫反应。此外，已发表的报告显示，吗啡可以增加培养的CD4+ T细胞产生IL-4。为了研究吗啡对CD4+ T细胞分化的影响，我们将使用转基因T细胞受体模型与直接检测吗啡对HIV疫苗免疫反应的影响相结合。通过这种方式，我们将能够将吗啡对T细胞介导的免疫反应的影响的详细机制研究与吗啡对HIV疫苗疗效的临床相关影响联系起来。在特定目的1中，我们将使用表达MHC ii类限制性T细胞受体（TCR）的小鼠系来检查吗啡对Th1/Th2谱系承诺的影响。我们将研究吗啡和抗原刺激如何同时给药影响体内Th1/Th2分化。然后，我们将测试之前的吗啡治疗是否可以改变抗原刺激后Th1/Th2的分化。我们还将研究是否可以通过改变细胞因子环境来逆转Th1/Th2谱系承诺的变化。在特定的目的2中，我们将检查CD8+ T细胞介导的免疫应答对DNA疫苗抗HIV。目前，抗艾滋病毒的DNA疫苗是最有可能用于人类的候选疫苗。我们将研究同时或先前使用吗啡对HIV DNA疫苗引起的免疫反应的影响。我们还将确定吗啡损害CD8+ T细胞介导的免疫所需的最小剂量间隔。完成这些目标将为吗啡在体内作用的详细机制研究奠定基础。公共卫生相关性：吗啡和其他滥用药物的使用是艾滋病毒感染的一个重要危险因素。此外，吗啡具有显著的免疫调节特性，可能会损害抗艾滋病毒疫苗的功效。我们的目标是了解吗啡影响控制HIV复制所需的免疫反应的机制。

DESCRIPTION (provided by applicant): In addition to being a risk factor for HIV infection, drug abuse can have a profound impact on the immunologic responses necessary for control of HIV replication. For example, CD8+ T cell-mediated immunity, which is critical for suppression of productive infection by HIV, is severely hampered by morphine. The goal of this research is to lay the foundation for mechanistic studies into how morphine regulates CD4+ T cell activation and differentiation. CD4+ T cell differentiation into the Th1 lineage and the subsequent activation and differentiation of HIV-specific CD8+ T cells is required for successful vaccination against HIV. Thus, accomplishing our goal will enable us to better understand how opiates might impair the efficacy of HIV vaccines. This understanding will better enable us to counsel prospective recipients of an HIV vaccine. We hypothesize that morphine induces permanent changes within naive CD4+ T cells such that, upon antigenic stimulation, the cells are "pre-programmed" to differentiate into the Th2 lineage. This hypothesis is based on our work using rhesus macaques that have been treated with morphine and infected with SIV. These monkeys were unable to mount a CD8+ T cell-mediated immune response. In addition, published reports showed that morphine can augment IL-4 production by CD4+ T cells in culture. To examine the effects of morphine on CD4+ T cell differentiation, we are combining the use of transgenic T cell receptor models with direct examination of the effects of morphine on immune responses to an HIV vaccine. In this way, we will be able to relate detailed mechanistic studies of the effects of morphine on T cell-mediated immune responses to clinically relevant effects of morphine on HIV vaccine efficacy. In specific aim 1, we will use a mouse line expressing an MHC class II-restricted T cell receptor (TCR) to examine the effects of morphine on Th1/Th2 lineage commitment. We will examine how concurrent administration of morphine and antigenic challenge affects Th1/Th2 differentiation in vivo. Then, we will test whether prior morphine treatment can alter Th1/Th2 differentiation following antigenic challenge. We will also examine whether the changes in Th1/Th2 lineage commitment can be reversed by altering the cytokine environment. In specific aim 2, we will examine CD8+ T cell-mediated immune responses to a DNA vaccine against HIV. Currently, DNA vaccines against HIV are the most likely candidates for human use. We will examine the effects of concurrent or previous use of morphine on the immune responses elicited by a DNA vaccine against HIV. We will also determine the minimal dosing interval of morphine required to impair CD8+ T cell-mediated immunity. Accomplishing these aims will lay the foundation for detailed mechanistic studies into the effects of morphine in vivo. PUBLIC HEALTH RELEVANCE: The use of morphine and other drugs of abuse is a significant risk factor for HIV infection. Further, morphine has dramatic immunoregulatory properties that can impair the efficacy of vaccines against HIV. Our goal is to understand the mechanisms by which morphine can influence the immune responses required for control of HIV replication.