COCAINE AND HIV1 IN CORONARY ENDOTHELIUM

描述：这个项目将研究可卡因对冠状动脉内皮细胞(CAEC)感染HIV-1的影响。最近的关键数据表明，HIV-1以流产的方式感染CAEC和脑微血管内皮细胞(BMVEC)，导致DNA合成强烈停止，可卡因增加了JR-FL株的这种流产感染，微血管内皮细胞表现出对CD4+、CXCR4和CCR5的调节。在CAEC和BMVEC中，可卡因和HIV-1诱导IL-6和细胞黏附分子，并增加内皮通透性。这些作用可能导致微血管内皮细胞泄漏，增加HIV-1的侵袭和白细胞向心脏间质的迁移。初步研究：他们先前已经证明，肿瘤坏死因子-α和可卡因引起微血管内皮细胞屏障，使HIV-1通过旁或跨细胞途径入侵，最近观察到HIV-1以流产方式感染CAEC，导致R/U5的逆转录，而不是进一步的逆转录步骤，但具有细胞内信号、IL-6诱导和细胞通透性增加。他们指出，可卡因和炎性细胞因子调节了HIV-1JR-FL的流产感染。他们推测：1)可卡因诱导IL-6、调节CXCR4和CCR5是介导CAEC流产感染和通透性增加的机制；2)流产的HIV-1感染、可卡因和IL-6的作用导致内皮屏障功能受损。具体目标：1)可卡因在CAEC流产感染中的作用；2)可卡因对HIV-1通过CAEC的途径和途径的影响；3)可卡因的信号、可卡因对IL-6的信号转导以及可卡因、HIV-1和IL-6对CCR5和CXCR4表达的影响；4)可卡因、HIV-1和IL-6对CAEC通透性、跨内皮细胞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.