HIV INFECTION IN CHILDREN OF IV DRUG ABUSERS

HIV感染中严重免疫缺陷的机制仍然存在 不清楚。关于HIV疾病发病机制的三个主要观察结果是：1) 是加速自发性淋巴细胞凋亡，这涉及到CD4和 CD8T细胞，2)存在细胞因子的异常分泌，并与 两种Th1型细胞因子IL-2的分泌减少和 干扰素-γ升高，以及3)存在持续的病毒复制 即使在临床潜伏期也是如此。此外，它一直是 在小鼠模型和人体内建立的CD4交联物(CD4XL) 导致活化诱导淋巴细胞死亡或凋亡。这 一项提案旨在测试这一假设，即在艾滋病毒感染中，异常 细胞因子分泌是致病的主要机制。 免疫无能，淋巴细胞因凋亡和数量减少而丧失 维持病毒载量。这一假设的基本原理是基于 HIV包膜蛋白GP与CD4分子连接的假设 120在体内发生，导致CD4XL，这是通过循环促进的 抗GP 120抗体。我们实验室的研究表明，如果CD4XL 在健康志愿者的外周血单核细胞中进行， 诱导细胞凋亡的发生。同时，Fas表达上调， 凋亡诱导抗原和细胞因子肿瘤坏死因子-α和干扰素-γ。 已知肿瘤坏死因子-α可上调潜伏感染患者的病毒表达 细胞，并在这一活动中与干扰素-γ协同作用。因此，这是合乎逻辑的 假设CD4XL不仅可以导致细胞凋亡，而且还可以导致肿瘤的扩散 细胞因子介导的潜伏感染激活病毒感染 细胞。这些观察，再加上我们之前的发现，艾滋病毒- T细胞内gpl2O/CD4相互作用导致IL-2合成受抑， 表明这可能是一种非常重要的功能机制 HIV感染中的无反应和淋巴细胞耗竭。在这 继续申请研究艾滋病毒感染儿童，我们将探索 细胞因子、病毒载量与细胞凋亡的相互关系 与患者的表型标志物和功能反应相结合 淋巴细胞。我们将把这些发现与患者的疾病联系起来。 使用明确定义的疾病进展标准的状况。在……里面 特别是，被归类为进步缓慢的儿童将与 快速进步者。更重要的是，我们将调查 各种生物制品具有逆转这些缺陷的能力。我们相信 对过程中涉及的致病机制的阐明 以上提到的应该有助于Rational的开发 这种疾病的治疗策略。

The mechanism for the profound immunodeficiency in HIV infection remains unclear. Three major observations in HIV disease pathogenesis are 1) there is accelerated spontaneous lymphocyte apoptosis, which involves CD4 and CD8 T cells, 2) there is aberrant cytokine secretion, with discordance in the secretion of the two Th1 type of cytokines, IL-2, which is reduced and IFN-gamma, which is increased and 3) there is persistent virus replication even in the period of clinical latency. Furthermore it has been established in the murine model and in man that CD4 crosslinking (CD4XL) results in activation induced lymphocyte cell death or apoptosis. This proposal aims to test the hypothesis that in HIV infection, aberrant cytokine secretion is a major pathogenic mechanism contributing to immunologic anergy, quantitative loss of lymphocytes by apoptosis and maintenance of viral load. The rationale for this hypothesis is based on the assumption that ligation of CD4 molecules by HIV envelope protein gp 120 occurs in vivo resulting in CD4XL which is facilitated by circulating anti-gp 120 antibodies. Studies in our laboratory have shown that if CD4XL is performed in peripheral blood mononuclear cells of healthy volunteers, induction of apoptosis occurs. Concurrently, there is upregulation of Fas, the apoptosis inducing antigen and of cytokines TNF-alpha and IFN-gamma. TNF-alpha is known to upregulate virus expression in latently infected cells, and synergizes with IFN-gamma in this activity. Thus it is logical to assume that CD4XL can lead not only to apoptosis but also to spread of virus infection by cytokine-mediated activation of latently infected cells. These observations, coupled with our prior findings that HIV- gpl2O/CD4 interaction in T cells leads to inhibition of IL-2 synthesis, indicates that this could be a highly significant mechanism for functional unresponsiveness and lymphocyte depletion in HIV infection. In this continuation application to study HIV-infected children, we will explore the inter-relationship between cytokines, virus load and apoptosis, coupled with phenotypic markers and functional responses in patients' lymphocytes. We will correlate these findings with the patients' disease status using well defined criteria for disease progression. In particular, children classified as slow progressors will be compared with rapid progressors. More importantly we will investigate the effect of various biologicals for their ability to reverse these defects. We believe that elucidation of the pathogenic mechanisms involved in the processes mentioned above should facilitate in the development of rational therapeutic strategies for this disease.