Conditional live HIV-1 variant to study immune activation and pathogenesis.

描述(申请人提供)：有充分的证据表明，持续和普遍的免疫激活，而不是艾滋病毒-1复制的直接影响，可能在艾滋病的发病机制和外周CD4+T细胞耗尽中发挥主要作用。这个问题需要进一步探讨，并具有重要的临床意义，因为免疫激活治疗需要添加到高效抗逆转录病毒治疗(HAART)中。尽管HAART将许多艾滋病毒感染者血浆中的病毒载量降低到无法检测到的水平，但最近的研究表明，病毒复制很可能以低水平继续下去。这种低水平的病毒复制可能会导致低水平的持久免疫激活，并可能发展为艾滋病。因此，要回答病毒的急性、高度复制或长期复制是否在建立持久免疫激活中起作用的问题，需要在病毒复制可以控制的模型中进行研究。我们实验室最近的两项发现，一种有条件的HIV-1活体变体(一种依赖DOX的HIV-RTTA，其中复制可以通过给药多西环素(DOX)来开启和关闭)2的开发，以及一种新的具有人类免疫系统的动物模型3，将使我们能够检验不同的病毒复制方案对免疫激活和HIV-1致病机制的影响。本提案代表了一种独特的合作方法来检验我们的假设，即持续免疫激活而不是HIV-1复制是导致HIV-1致病的主要因素。由于Treg在控制免疫反应中起着重要作用，我们还将研究Treg对HIV-1诱导的免疫激活的影响。目前尚不清楚Treg在HIV-1感染期间对免疫系统是有害还是有利。我们假设Treg在HIV-1感染中调节失调，导致胸腺产生的功能Treg耗尽。Treg的减少可能导致免疫激活和免疫病理。具体地说，我们将研究：1.评估可诱导的HIV-1对人类免疫系统(His)-RAG2-/-YC-/-小鼠胸腺和外周免疫激活和发病的影响。2.探讨调节性T细胞(Treg)在控制HIV-1诱导的免疫激活中的作用。从拟议的实验中获得的信息将提高我们对持续免疫激活在HIV-1发病机制中的作用的理解，并对HIV-1感染者的新治疗具有潜在的意义。

DESCRIPTION (provided by applicant): There is ample evidence that a persistent and generalized immune activation, more than the direct effect of HIV-1 replication, may play a major role in AIDS pathogenesis and peripheral CD4+ T cell depletion. This question needs to be further explored and has important clinical implications, because treatment of immune activation would need to be added to highly active antiretroviral therapy (HAART). Although HAART decreases viral loads to undetectable levels in plasma in many HIV-infected individuals, recent studies indicate that that viral replication likely continues at low levels. This low level viral replication could lead to low persistent immune activation and the possible progression to AIDS. Therefore, to answer the question whether an acute and high or a prolonged viral replication plays a role in the establishment of persistent immune activation, studies need to be done in models where viral replication can be controlled. Two recent findings in our laboratories, the development of a conditional live HIV-1 variant (a dox-dependent HIV-rtTA, in which the replication can be switched on and off by the administration of doxycyline (dox))2, and a novel animal model with a human immune system 3, will allow us to examine the impact of different schemes of viral replication on immune activation and HIV-1 pathogenesis. The present proposal represents a unique collaborative approach to test our hypothesis that persistent immune activation, rather than HIV-1 replication, is a major factor leading to HIV-1 pathogenesis. As Treg play an important role in controlling immune responses, we will also examine the impact of Treg on HIV-1 induced immune activation. It is still unclear whether Treg have detrimental or favorable effects on the immune system during HIV-1 infection. We hypothesize that Treg are dysregulated in HIV-1 infection, resulting in depletion of functional Treg generated in the thymus. A decrease in Treg may lead to immune activation and immunopathology. Specifically we will examine: 1. To evaluate the impact of an inducible HIV-1 on immune activation and pathogenesis in the thymus and periphery of Human Immune System (HIS)-RAG2-/-yc-/- mice. 2. To investigate the role of regulatory T cells (Treg) in controlling HIV-1 induced immune activation. Information gained from the proposed experiments will improve our understanding of the role of persistent immune activation in HIV-1 pathogenesis and has potential implications for novel treatments of HIV-1 infected individuals.