IMMUNE AND THERAPEUTIC SUPPRESSION OF HIV IN THE LUNG

肺是受艾滋病毒影响的主要器官之一。在早期艾滋病毒中 感染，在肺细胞中检测到很少的病毒，但在晚期疾病中 (当剩余的CD4+T细胞很少时)体内的病毒数量 肺可以变得很坚固。抗逆转录病毒治疗对缺氧缺血性脑病的影响 肺中的复制还不是很清楚。该项目将研究 这些问题通过四个目的：(1)通过分析艾滋病毒的数量 支气管肺泡灌洗前后细胞及肺泡灌洗液中的含量 用病毒蛋白水解酶的快速起作用的抑制物(如 Indinavir)，测量肺中病毒基因组的半衰期 将会被获得。假设在此之前存在一个稳态 治疗，这将允许计算每天产生的病毒 在HIV疾病的不同阶段的受试者的肺部。(2)由 分析病毒POL区域的序列(包括反向 转录酶和蛋白水解酶)是目前可用的 药物方面，将对肺内耐药突变的进化进行研究。 通过将这些序列与从病毒基因组中获得的序列进行比较 血液，就有可能估计病毒感染的程度 肺上的复制反映了血液中的复制，或者艾滋病毒是否可以 在肺中自主复制，不受全身影响 对血液中的病毒进化有选择性的影响。(3)一把钥匙 对肺的细胞免疫反应是CD40的表达 配体(CD40L)，这对控制感染是至关重要的，如 卡氏拟青霉。CD40L诱导巨噬细胞表达CD40和 对CD40L的反应将被研究。(4)最后，细胞因素 (例如，来自CD8+T细胞)和存在于支气管肺泡的可溶性因子 抑制HIV复制的灌洗液(如SLPO1、趋化因子) 将对肺部进行研究，并将其与艾滋病毒在肺部的复制相关联 (来自上述目标1)控制艾滋病毒在肺部复制的系统将是 更好地理解，以及艾滋病毒在肺部的演变 抗逆转录病毒药物将被定义。所获得的知识可能表明 利用改进的策略抑制HIV在肺部的复制 免疫调节剂和治疗剂，这可能会导致更好的控制 关于艾滋病毒感染的肺部并发症。

The lung is one of the major organs affected by HIV disease. In early HIV infection, little virus is detectable in lung cells, but in late disease (when there are few remaining CD4 + T cells) the amount of virus in the lung can become substantial. The effect of antiretroviral therapy on HIB replication in the lung is not well understood. This project will study these issues through four aims; (1) By analyzing the quantity of HIV present in bronchoalveolar lavage cells and fluid both before and after treatment with a rapidly acting inhibitor of the viral protease (such as indinavir), measurements of the half-life of the viral genome in the lung will be obtained. Assuming that a steady-state was present prior to therapy, this will allow the calculation of the daily production of virus in the lung in subjects at different stages of HIV disease. (2) By analyzing the sequences of the viral pol region (which includes reverse transcriptase and protease) that is the target of currently available drugs, the evolution of drug resistant mutants in the lung will be studied. By comparing these sequences with those obtained from viral genomes in the blood, it will be possible to estimate the degree to which viral replication on the lung mirrors that in the blood or whether HIV can replicate autonomously in the lung independent of the systemic influences that have a selective effect on viral evolution in the blood. (3) A key to the cellular immune response in the lung is the expression of CD40 ligand (CD40L), which is critical for the control of infections such as Pneymocystis carnii. CD40L induces macrophages to express CD40 and to respond to CD40l will be studied. (4) Finally, the cellular factors (e.g., from CD8 + T cell) and soluble factors present in bronchoalveolar lavage fluid (e.g., SLPO1, chemokines) that suppress HIV replication in the lung will be studied and correlated with the replication of HIV in the lung (from Aim 1 above) system to control HIV replication in the lung will be better understood, and the evolution of HIV in the lung in response to antiretroviral drugs will be defined. The knowledge gained may suggest improved strategies for suppressing HIV replication in the lung utilizing immune modulators and therapeutic agents, which may lead to better control of the pulmonary complications of HIV infections.