CARDIOMYOPATHY, HIV1 AND CHEMOKINES

心肌病、HIV-1和趋化因子随着生存率的提高，HIV-1感染越来越复杂，心肌病与心脏组织中的炎性浸润和HIV-1核酸有关。本提案的总体目标是确定HIV-1、趋化因子和趋化因子受体在HIV-1心肌病中的作用。我们的初步工作表明，冠状动脉内皮细胞（CAEC）和心脏组织中存在CCR 5，CXCR 4和其他趋化因子受体，以及CAEC和单核细胞在适当刺激下分泌趋化因子。我们的数据还表明，HIV-1感染CAEC流产和诱导IL-6。趋化因子受体可能决定这种流产感染。在这次流产的感染之后。在这种流产感染之后，由CAEC释放的趋化因子可能是心脏的单核细胞/巨噬细胞浸润的关键介质，并且IL-6可能损害CAEC的屏障功能。我们的假设是，在病毒性心肌病中，（a）HIV-1引起内皮细胞的失败感染和内皮下组织的转胞侵入，这两者都可以通过CAEC上趋化因子受体的存在来确定，（B）在内皮和内皮下心脏组织中，HIV-1诱导趋化因子，其吸引单核细胞和淋巴细胞的迁移，和（c）感染的单核细胞/巨噬细胞释放毒性因子，其引起心肌细胞炎症和凋亡，并可能引起心脏肥大。具体目标是：#1在体内和体外定位CAEC和心肌中趋化因子受体在基础状态和用HIV-1或HIV-1肽刺激后的表达，并确定它们在流产感染中的作用，#2证明CC-和CXC-趋化因子在单核细胞穿过CAEC屏障的迁移中的作用;#3鉴定由HIV-1感染或重组病毒蛋白刺激的单核细胞和巨噬细胞的上清液中负责心肌细胞的炎症和凋亡的因子。本工作将阐明（1）流产的HIV-1感染和趋化因子在单核细胞向心脏组织迁移中的作用，（2）由推定的单核细胞/巨噬细胞衍生毒素或病毒蛋白的直接毒性作用引起的HIV-1心肌病中的心肌细胞损伤机制，（3）由刺激的心肌细胞分泌的趋化因子、细胞因子和其他产物对心肌损伤的贡献。这项研究的结果可能会导致开发新的策略来预防或改善艾滋病毒感染对心脏的影响。

Cardiomyopathy, HIV-1 and chemokines With greater survival, HIV-1 infection is increasingly complicated by cardiomyopathy, which is associated with inflammatory infiltrates and HIV-1 nucleic acids in the heart tissues. The overall objective of this proposal is to determine the roles of HIV-1, chemokines and chemokine receptors in HIV-1 cardiomyopathy. Our preliminary work shows the presence of CCR5, CXCR4, and other chemokine receptors on coronary artery endothelial cells (CAEC) and in heart tissues, and chemokine secretion by CAEC and monocytes upon appropriate stimulation. Our data also indicate that HIV-1 infects CAEC abortively and induces IL-6. Chemokine receptors are likely to determine this abortive infection. Following on this abortive infection. Following on this abortive infection, chemokines released by CAEC may by crucial mediators of monocyte/macrophage infiltration of the heart and IL-6 may impair the barrier function of CAEC. Our hypothesis are that in viral cardiomyopathy (a) HIV-1 causes abortive infection of endothelial cells and transcytotic invasions of subendothelial tissues, both of which may be determined by the presence of chemokine receptors on CAEC, (b) in the endothelial and subendothelial heart tissues, HIV-1 induces chemokines, which attract immigration of monocytes and lymphocytes, and (c) infected monocyte/macrophages release toxic factors, which cause cardiomyocyte inflammation and apoptosis, and possibly cardiac hypertrophy. The specific aims are to: #1 localize in vivo and in vitro the expression of chemokine receptors in CAEC and the myocardium in basal state and after stimulation with HIV-1 or HIV-1 peptides, and to determine their role in abortive infection, #2 demonstrate the role of CC- and CXC-chemokines in monocyte transmigration across the CAEC barrier; #3 identify the factors in the supernatants from monocyte and macrophages stimulated by HIV-1 infection or recombinant viral proteins that are responsible for inflammation and apoptosis of cardiomyocytes. This work will elucidate (1) the role of abortive HIV-1 infection and chemokines in transmigration of monocytes into heart tissues, (2) the mechanisms of damage to myocytes in HIV-1 cardiomyopathy caused by putative monocyte/macrophage-derived toxins or direct toxic effects of viral proteins, (3) the contribution of chemokines, cytokines and other products secreted by stimulated myocytes to myocardial injury. The results of this research could lead to development of new strategies for preventing or ameliorating the effects of HIV infection on the heart.