CHEMOKINES AND HIV REPLICATION IN ALVEOLAR MACROPHAGES

感染艾滋病毒往往导致艾滋病的发展。 这表现 随着机会性感染的发展，其中许多发生在 肺 肺泡巨噬细胞（AM）是肺泡内主要的常驻炎症细胞， 肺细胞和肺防御外来抗原和微生物的防御者。 虽然AM很容易被HIV感染，但该病毒相对 潜伏在这些细胞中直到疾病晚期 的目标 这项建议是研究C-C趋化因子在调节中的作用 艾滋病病毒复制在AM。 我们实验室的初步数据表明 C-C趋化因子，特别是RANTES，减少HIV复制， 外周血单核细胞（PBM）和AM。 当受试者的AM 无症状HIV感染者合成这些C-C能力增加 趋化因子，CD 4计数低且患有症状性肺部疾病的受试者 表现出降低的能力。 我们的实验室已经证明， 趋化因子水平由花生四烯酸（AA）代谢物调节。 前列腺素（PG）增加和白三烯（LT）合成减少 在AM中，随着HIV疾病的进展而发生， 趋化因子水平，从而增加艾滋病毒复制。 这个假设是 C-C趋化因子水平，尤其是RANTES， 调节AM中的HIV复制。 本提案的具体目标 目的是（1）确定外源性C-C趋化因子是否调节HIV复制 在上午。 此外，（2）内源性C-C趋化因子在 将检查AM中HIV复制的调节。 此外，（3） RANTES和其他C-C趋化因子调节HIV的分子机制 将研究复制。 实验方法将是研究 C-C趋化因子在AM、PBM和THP-1中对HIV感染的影响 单核细胞系 AM也将从HIV感染受试者中获得。 将探索外源性C-C趋化因子对HIV复制的影响。 此外，内源性C-C趋化因子在AM中HIV复制中的作用 将通过使用中和抗体和操纵PG进行检查 LT水平。 趋化因子调控HIV的分子机制 复制，包括（1）阻断共享受体或（2）影响 将研究转录调控。 总而言之，这一提议 将有助于确定HIV复制的调节机制， C-C趋化因子在AM中的作用，并增强我们对AM的理解和能力， 控制肺部的艾滋病毒感染。

Infection with HIV often leads to the development of AIDS. This manifests with the development of opportunistic infections, many of which occur in the lung. The alveolar macrophage (AM) is the main resident inflammatory cell and defender of the lung against foreign antigens and microbes. Although AM are readily infected by HIV, the virus remains relatively dormant within these cells until late in the disease. The objective of this proposal is to examine the role C-C chemokines play in the regulation of HIV replication in AM. Preliminary data from our laboratory suggest that the C-C chemokines, especially RANTES, reduce HIV replication in peripheral blood monocytes (PBM) and AM. Whilst AM from subjects with asymptomatic HIV infection have increased capacity to synthesize these C-C chemokines, subjects with low CD4 counts with symptomatic lung disease demonstrate a reduced capacity. Our laboratory has demonstrated that C-C chemokine levels are regulated by arachidonic acid (AA) metabolites. Increases in prostaglandin (PG) and reduction in leukotrine (LT) synthesis in AM, which occurs with progression of HIV disease, may reduce C-C chemokine levels, and hence increase HIV replication. The hypothesis is that levels of C-C chemokines, especially RANTES, contribute to the regulation of HIV replication in AM. The specific aims of this proposal are (1) to determine if exogenous C-C chemokines regulate HIV replication in AM. In addition, (2) the role of endogenous C-C chemokines ina the regulation of HIV replication in AM will be examined. Furthermore, (3) the molecular mechanisms by which RANTES and other C-C chemokines regulate HIV replication will be studied. The experimental approach will be to study the effect of C-C chemokines on HIV infection in AM, PBM, ant the THP-1 monocytic cell line. AM will also be obtained from HIV-infected subjects. The effect of exogenous C-C chemokines on HIV replication will be explored. In addition, the role of endogenous C-C chemokines on HIV replication in AM will be examined by utilizing neutralizing antibodies and manipulating PG and LT levels. Molecular mechanisms of chemokine regulation of HIV replication including (1) blocking a shared receptor or (2) affecting transcriptional regulation will be investigated. In summary, this proposal will help determine the mechanisms by which HIV replication is regulated by C-C chemokines in AM, and enhance our understanding of and our ability to control HIV infection in the lung.