Studies of the Pathogenic Mechanism of HIV

描述（由申请人提供）：尽管有许多关于HIV如何导致CD 4淋巴细胞耗竭的理论，但三种似乎是最可行的。第一种说法是，HIV导致“整体免疫失活”，伴随着活化诱导的CD 4淋巴细胞死亡的增加，导致它们最终耗尽。第二种说法是，艾滋病毒阻碍了新的CD 4淋巴细胞的产生，导致它们最终消失。第三种说法是HIV的致病机制是在静息的CD 4淋巴细胞（不允许病毒复制）上，其与HIV包被的滤泡树突细胞或淋巴组织中的生产性感染细胞接触，从而发出信号，导致在进入血流后增强的归巢回到淋巴结（LN），并上调Fas。这些细胞在归巢过程中被二次发出信号，这导致其中许多细胞的凋亡诱导。这些理论中的每一个都具有独特的特征，可以进行某些预测，这些将在HIV+受试者中进行探索。我们的总体假设是，这些理论之一将是HIV耗尽CD 4淋巴细胞的主要机制，并且三个具体目标将解决该假设：（1）定量Ki 67+的HIV患者的LN活检中死亡的CD 4淋巴细胞的频率（即，被激活并且正在经历“激活诱导的细胞死亡”）或者是胸苷磷酸化酶+（即，是通过病毒接触发出信号的静止细胞）;（2）与感染病毒（HBV、HCV）的患者相比，定量HIV患者血液中新的CD 4淋巴细胞的频率，所述病毒感染不会导致CD 4淋巴细胞的耗竭;和（3）定量HIV患者LN活检中死亡的CD 4淋巴细胞的频率，所述LN活检表达归巢受体信号传导的标志物。这些体内研究应该澄清这些机制中的每一个在HIV患者中的相对重要性。

DESCRIPTION (provided by applicant): Although there are numerous theories concerning how HIV causes depletion of CD4 lymphocytes, three appear to be the most viable. The first states that HIV causes "global immune inactivation" with the concomitant increase in activation-induced cell death of CD4 lymphocytes, leading to their eventual exhaustion. The second states that HIV retards production of new CD4 lymphocytes, leading to their eventual disappearance. The third states that HIV's pathogenic mechanism is on resting CD4 lymphocytes (non-permissive for virus replication), which come into contact with HIV-coated follicular dendritic cells or productively infected cells in lymphoid tissues and are thereby signaled, resulting in enhanced homing back to lymph nodes (LNs), after entering the blood stream, and upregulation of Fas. These cells are secondarily signaled during the homing process, which leads to induction of apoptosis in many of them. Each of these theories has unique features which allow certain predictions, and these will be explored in HIV+ subjects. Our overall hypothesis is that one of these theories will be the predominant mechanism of HIV depletion of CD4 lymphocytes, and three specific aims will address this hypothesis: (1) to quantitate the frequencies of dying CD4 lymphocytes in LN biopsies of HIV patients that are Ki67+ (i.e., are activated and are undergoing "activation-induced cell death") or are thymidine phosphorylase+ (i.e., are resting cells signaled by virus contact); (2) to quantitate the frequencies of new CD4 lymphocytes in the blood of HIV patients in comparison to patients infected with viruses (HBV, HCV) which do not lead to depletion of CD4 lymphocytes; and (3) to quantitate the frequencies of dying CD4 lymphocytes in LN biopsies of HIV patients which express markers of homing receptor signaling. These in vivo studies should clarify the relative importance of each of these mechanisms in HIV patients.