HIV INFECTION IN CHILDREN OF IV DRUG ABUSERS

艾滋病毒感染中严重免疫缺陷的机制仍然是 不清楚HIV疾病发病机制的三个主要观察结果是：1） 是加速自发淋巴细胞凋亡，涉及CD 4和 CD 8 T细胞，2）存在异常的细胞因子分泌， 两种Th 1型细胞因子IL-2的分泌减少， IFN-γ，其增加和3）存在持续的病毒复制 即使在临床潜伏期。此外， 在小鼠模型和人中建立，CD 4交联（CD 4XL） 导致活化诱导的淋巴细胞死亡或凋亡。这 这项提案旨在检验一种假设，即在艾滋病毒感染中， 细胞因子分泌是一种主要的致病机制， 免疫无反应性，细胞凋亡导致的淋巴细胞数量损失， 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CD 4分子连接假设 120在体内发生，导致CD 4XL，其通过循环促进 抗gp 120抗体。我们实验室的研究表明，如果CD 4XL 在健康志愿者的外周血单核细胞中进行， 发生凋亡诱导。同时，Fas表达上调， 细胞凋亡诱导抗原和细胞因子TNF-α和IFN-γ。 已知TNF-α在潜伏感染的细胞中上调病毒表达。 细胞，并与IFN-γ协同作用。因此， 假设CD 4XL不仅可以导致细胞凋亡，还可以导致肿瘤的扩散， 病毒感染，通过奎宁介导的潜伏感染的激活 细胞这些观察结果，加上我们先前的发现，艾滋病毒- T细胞中的gp 120/CD 4相互作用导致IL-2合成的抑制， 表明这可能是一个非常重要的机制， HIV感染中的免疫反应迟钝和淋巴细胞耗竭。 在这 继续申请研究艾滋病病毒感染儿童，我们将探讨 细胞因子、病毒载量和细胞凋亡之间的相互关系， 再加上患者的表型标记和功能反应， 淋巴细胞 我们将把这些发现与病人的疾病联系起来 使用明确定义的疾病进展标准进行评估。 在 特别是，将被归类为缓慢进展者的儿童与 快速进步者 更重要的是，我们将研究 各种生物制剂逆转这些缺陷的能力。我们认为 阐明了这些过程中的致病机制， 以上所述，应有助于发展合理的 针对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.