HIV INFECTION/COCAINE EFFECT ON CARDIOVASCULAR PATHOLOGY

HIV 感染/可卡因对心血管病理的影响

• 批准号: 6537625
• 负责人: Aftab A. Ansari
• 金额: $ 30.4万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-01 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6537625
• 关键词: HIV infections; cardiovascular disorder; catecholamines; cell cell interaction; cell proliferation; cocaine; cytomegalovirus; disease /disorder etiology; drug abuse; drug interactions; gene expression; human immunodeficiency virus 1; latent virus infection; metalloendopeptidases; pathologic process; simian immunodeficiency virus; tissue /cell culture; vascular endothelium; vascular smooth muscle

The etiology of HIV-related cardiovascular disease (CVD) specially in patients with a history of cocaine use is most likely multifactorial. This is highlighted by the finding that there is an increase in the incidence of CVD in individuals with a history of cocaine abuse who are not HIV-1 infected and a similar increase in CVD in HIV-1 infected individuals who have no history of drug use. In addition, marked vascular lesions have been documented in SIV infected juvenile rhesus macaques who have no history of drug use. Thus, the effects of cocaine and HIV-1 infection leading to CVD may operate by separate but overlapping pathways, synergistically accelerating the disease process. It is our working hypothesis that insult to the vascular endothelium is one of the factor that contributes to CVD in HIV-1 infection which is further exacerbated by the use of drugs such as cocaine. Our lab has been studying the biology of lymphoid-endothelial cell interaction in both humans and non-human primates (NHP) in a variety of settings including responses to viral infections. During this process we have acquired unique sets of reagents, tools, techniques, knowledge, experience and important preliminary data which we submit will aid in defining some of the mechanisms of pathogenesis of HIV and cocaine induced cardiac disease. Specifically, we propose to a) determine if HIV/SIV infected lymphoid cells show increased adherence to human and NHP microvascular endothelial cells (MVEC), respectively in the presence/absence of cocaine/catecholamines using both a static and dynamic culture system b) to define the effect of HIV/SIV infected lymphoid cells in the presence and absence of cocaine/catecholamine on the expression of select cell adhesion/costimulatory molecule (CAM/CSM's), cytokines and chemokines by human and NHP MVEC c) determine if the effect on CAM/CSM's, cytokines and chemokines requires a disease inducing lentivirus isolate d) determine if HIV infected lymphoid cells in the presence/absence of cocaine/catecholamine induces the breakdown of latency in latent CMV infected autologous aortic endothelial cells e) determine if co-culture of MVEC and autologous smooth muscle cells (SMC's) in the presence of cocaine/catecholamine alone, HIV/SIV infected autologous cells alone or in combination leads to SMC proliferation and remodeling and, f) determine whether interaction of HIV-1/SIV infected cells alone and/or in the presence of cocaine/catecholamine leads to the synthesis of metalloproteinases. We reason that such studies may provide unique insights on the relationship between the effects of cocaine and HIV infection in the pathogenesis of cardiovascular disease.

HIV相关心血管疾病（CVD）的病因，特别是在有可卡因使用史的患者中，很可能是多因素的。 这一发现突出表明，在没有HIV-1感染的有可卡因滥用史的个体中CVD的发病率增加，在没有吸毒史的HIV-1感染者中CVD的发病率类似增加。 此外，在没有药物使用史的SIV感染的幼年恒河猴中记录了显著的血管病变。 因此，可卡因和HIV-1感染导致CVD的作用可能通过单独但重叠的途径起作用，协同加速疾病进程。 我们的工作假设是，血管内皮损伤是导致HIV-1感染中CVD的因素之一，而使用可卡因等药物会进一步加剧CVD。我们的实验室一直在研究人类和非人类灵长类动物（NHP）在各种环境中淋巴细胞-内皮细胞相互作用的生物学，包括对病毒感染的反应。在这一过程中，我们获得了一套独特的试剂、工具、技术、知识、经验和重要的初步数据，我们提交的这些数据将有助于确定艾滋病毒和可卡因引起的心脏病的发病机制。 具体而言，我们建议a）确定HIV/SIV感染的淋巴样细胞是否显示出对人和NHP微血管内皮细胞（MVEC）的粘附增加，B）以确定在可卡因/儿茶酚胺存在和不存在下HIV/SIV感染的淋巴样细胞对选择的细胞粘附/共刺激分子表达的影响c）确定是否对CAM/CSM的影响，细胞因子和趋化因子需要疾病诱导慢病毒分离物d）确定在可卡因/儿茶酚胺存在/不存在下HIV感染的淋巴样细胞是否诱导潜伏CMV感染的自体主动脉内皮细胞中潜伏期的破坏e）确定MVEC和自体平滑肌细胞（SMC）在单独可卡因/儿茶酚胺存在下，HIV/SIV感染的自体细胞单独或组合导致SMC增殖和重塑，和f）确定HIV-1/SIV感染的细胞单独和/或在可卡因/儿茶酚胺存在下的相互作用是否导致金属蛋白酶的合成。 我们的理由是，这些研究可能提供独特的见解可卡因和艾滋病毒感染的影响之间的关系，在心血管疾病的发病机制。