CHEMOKINES AND HIV REPLICATION IN ALVEOLAR MACROPHAGES

感染艾滋病毒往往会导致艾滋病的发展。这体现了 随着机会性感染的发展，其中许多发生在 肺部。肺泡巨噬细胞(AM)是主要的滞留性炎症细胞 肺的细胞和防御者，抵御外来抗原和微生物。 虽然AM很容易感染艾滋病毒，但病毒仍然相对 在这些细胞内休眠，直到疾病晚期。的目标是 这项建议是为了研究C-C趋化因子在调节中所起的作用 AM中的HIV复制我们实验室的初步数据显示 C-C趋化因子，特别是RANTES，减少HIV在体内的复制 外周血单核细胞(PBM)和AM而AM则来自于 无症状HIV感染增加了合成这些C-C的能力 趋化因子与有症状性肺部疾病的低CD4细胞受试者 展示减少的容量。我们的实验室已经证明了C-C 趋化因子水平受花生四烯酸(AA)代谢产物的调节。 前列腺素(PG)增加和白三氨酸(LT)合成减少 随着HIV疾病的进展而发生的AM，可能会降低C-C 趋化因子水平，从而增加艾滋病毒复制。假设是 C-C趋化因子的水平，特别是RANTES，有助于 AM中HIV复制的调控这项建议的具体目的 是(1)确定外源性C-C趋化因子是否调节HIV复制 在AM中此外，(2)内源性C-C趋化因子在血管紧张素转换酶中的作用 本课程将研究AM中HIV复制的调控。此外，(3) RANTES等C-C趋化因子调控HIV的分子机制 将对复制进行研究。实验方法将是研究 C-C趋化因子对AM、PBM和THP-1中HIV感染的影响 单核细胞系。AM也将从艾滋病毒感染者那里获得。 我们将探讨外源性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 和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 将对转录调控进行调查。总而言之，这项提案 将有助于确定艾滋病毒复制的调控机制 C-C趋化因子在AM中的作用，并增强我们对AM的认识和能力 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.