TRANSGENIC MICE--MODEL FOR STUDYING HIV INFECTION OF THE

大约20%的HIV-1感染者会发生与大脑中HIV-1感染细胞相关的神经系统疾病。 高活性抗逆转录病毒疗法（HAART）在显著降低血浆病毒载量方面的有效性提高了HIV感染可能被成功地从全身免疫系统中“清除”的可能性。 然而，大脑中的HIV-1感染细胞可能是一个重要的储存库，在停止抗逆转录病毒治疗后，HIV可以从该储存库重新引入淋巴组织。因此，我们建议确定大脑是否可以作为HIV-1感染细胞的体内避难所，例如可以从大脑迁移并感染外周淋巴组织的小胶质细胞。此外，我们将研究一种新的治疗方法的体内有效性，该方法包括HAART与靶向毒素治疗相结合，以减少大脑中HIV-1感染细胞的数量。我们还建议研究HIV-1感染细胞在体内进入大脑的机制。虽然我们对HIVD的临床表现了解很多，但在我们对该疾病的病理生理学的理解中存在许多空白，包括HIV穿过血脑屏障的机制。有很多数据支持HIV-1感染是通过HIV- 1感染细胞的浸润进入大脑的可能性。我们将研究HIV-1感染的细胞进入的机制，通过研究不同的因素，如细胞活化，趋化因子的产生和细胞因子分泌对HIV-1感染的细胞迁移到大脑的体内影响。从这些研究中产生的信息应该提供深入了解细胞贩运到大脑中的机制，这可能允许开发和体内测试旨在防止HIV-1感染细胞进入大脑的新治疗策略。阻断HIV-1感染的细胞迁移到大脑中可能是一种重要的新的治疗策略，可用于急性感染者和HIV-1感染母亲所生的婴儿。这些体内研究将使用我们最近开发的新型转基因小鼠模型进行，这些模型显示了生产性HIV-1感染。

Approximately 20% of HIV-1-infected infected individuals develop neurological disease associated with the presence of HIV-1-infected cells in the brain. The effectiveness of high activity antiretroviral therapy (HAART) in markedly reducing plasma viral loads has raised the possibility that HIV infection may be successfully "purged" from the systemic immune system. However, HIV-1-infected cells in the brain may function as an important reservoir from which HIV can be reintroduced back into the lymphoid tissues after cessation of anti-retroviral therapy. Therefore, we propose to determine if the brain can function as an in vivo sanctuary for HIV-1-infected cells such as microglia that can migrate from the brain and infect peripheral lymphoid tissues. In addition, we will examine the in vivo effectiveness of a novel therapeutic approach consisting of HAART combined with targeted toxin therapy to reduce the numbers of HIV-1-infected cells in the brain. We also propose to study the mechanisms of the in vivo trafficking of HIV-1-infected cells into the brain. Although much is known about the clinical manifestations of HIVD, there are many gaps in our understanding of the pathophysiology of the disease including the mechanism by which HIV crosses the blood brain barrier. There is much data to support the possibility that HIV-1 infection is introduced into the brain by the infiltration of HIV- 1-infected cells. We will examine the mechanism of entry of HIV-1- infected cells by investigating the in vivo effect of different factors such as cellular activation, chemokine production and cytokine secretion on the migration of HIV-1-infected cells into the brain. Information generated from these studies should provide insights into the mechanism of cellular trafficking into the brain that may permit the development and in vivo testing of new therapeutic strategies aimed at preventing entry of HIV-1-infected cells into the brains. Blocking the migration of HIV-1-infected cells into the brain may be an important new therapeutic strategy to use for acutely infected individuals and for infants born to HIV-1-infected mothers. These in vivo studies will be performed using novel transgenic mouse models that we have recently developed that display productive HIV-1 infection.