COCAINE AND HIV1 IN CORONARY ENDOTHELIUM

本项目将研究可卡因对冠状动脉内皮细胞（CAEC） HIV-1感染的影响。最近的关键数据表明，HIV-1以流产方式感染CAEC和脑微血管内皮细胞（BMVEC），导致强阻断DNA合成，可卡因增加JR-FL菌株的这种流产感染，微血管内皮细胞显示CD4+， CXCR4和CCR5的调节。在CAEC和BMVEC中，可卡因和HIV-1诱导IL-6和细胞粘附分子，增加内皮通透性。这些影响可能导致微血管内皮渗漏，增加HIV-1入侵和白细胞向心脏间质转移。初步研究：他们先前已经证明tnf - α和可卡因引起微血管内皮屏障，允许HIV-1通过旁或跨细胞途径入侵，最近观察到HIV-1感染CAEC失败导致R/U5的逆转录，而不需要进一步的逆转录步骤，但细胞内信号传导，IL-6诱导和细胞通透性增加。他们注意到可卡因和炎性细胞因子可调节HIV-1JR-FL流产感染。他们假设1)流产感染和CAEC渗透性增加是由可卡因诱导IL-6和调节CXCR4和CCR5介导的，2)流产HIV-1感染、可卡因和IL-6的作用导致内皮屏障功能受损。具体目的：他们将确定1)可卡因对CAEC流产感染的影响，2)可卡因对HIV-1穿过CAEC的通道和途径的影响，3)可卡因的信号传导，可卡因对IL-6的信号传导，可卡因，HIV-1和IL-6对CCR5和CXCR4表达的影响，以及4)可卡因，HIV-1和IL-6对CAEC通透性，跨内皮电阻和促凝活性的影响。

DESCRIPTION: (Adapted from Applants Abstracts) This project will examine the effects of cocaine on HIV-1 infection of coronary artery endothelial cells (CAEC). Recent pivotal data suggest that HIV-1 infects CAEC and brain microvascular endothelial cells (BMVEC) in an abortive fashion leading to strong-stop DNA synthesis, cocaine increases this abortive infection with the JR-FL strain, and microvascular endothelial cells display modulation of CD4+, CXCR4 and CCR5. In CAEC and BMVEC, cocaine and HIV-1 induce IL-6 and cell adhesion molecules, and increases endothelial permeability. These effects may lead to microvascular endothelial leaks and to increased HIV-1 invasion and leukocyte transmigration into the heart interstitium. Preliminary studies: They have previously demonstrated that TNF-alpha and cocaine cause the microvascular endothelial barriers to allow HIV-1 invasion by a para- or transcellular route and have recently observed that HIV-1 infects CAEC abortively leading to reverse transcription of R/U5 without further steps of reverse transcription but with intracellular signaling, IL-6 induction and increase in cell permeability. They have noted that cocaine and inflammatory cytokines modulate the abortive infection by HIV-1JR-FL. They hypothesize that 1) the abortive infection and increased permeability of CAEC are mediated by cocaine's induction of IL-6 and modulation of CXCR4 and CCR5, and 2) the effects of the abortive HIV-1 infection, cocaine, and IL-6 result in an impairment of endothelial barrier function. Specific Aims: They will determine 1) the effects of cocaine on the abortive infection of CAEC, 2) the effects of cocaine on passage and route of HIV-1 across CAEC, 3) cocaine's signaling, cocaine's signaling for IL-6, and the effects of cocaine, HIV-1 and IL-6 on CCR5 and CXCR4 expression, and 4) the effects of cocaine, HIV-1 and IL-6 on permeability, transendothelial electrical resistance, and procoagulant activity in CAEC.