HIV INFECTION/COCAINE EFFECT ON CARDIOVASCULAR PATHOLOGY

hiv相关心血管疾病（CVD）的病因，特别是有可卡因使用史的患者，很可能是多因素的。有可卡因滥用史的非HIV-1感染者的心血管疾病发病率增加，无药物使用史的HIV-1感染者的心血管疾病发病率也有类似增加，这一发现突出了这一点。此外，在没有药物使用史的SIV感染的幼年恒河猴中也有明显的血管病变。因此，可卡因和HIV-1感染导致心血管疾病的影响可能通过不同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，对血管内皮的损害是导致HIV-1感染中心血管疾病的因素之一，而使用可卡因等药物会进一步加剧心血管疾病的感染。我们的实验室一直在研究人类和非人灵长类动物（NHP）在各种环境下淋巴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诱发心脏病的一些发病机制。具体来说，我们建议a)使用静态和动态培养系统确定HIV/SIV感染的淋巴细胞是否分别在存在/不存在可卡因/儿茶酚胺的情况下对人类和NHP微血管内皮细胞（MVEC）的粘附性增加；b)确定存在和不存在可卡因/儿茶酚胺的HIV/SIV感染淋巴细胞对选定细胞粘附/共刺激分子（CAM/CSM’s）表达的影响。c)确定对CAM/CSM、细胞因子和趋化因子的影响是否需要诱导疾病的慢病毒分离物d)确定在存在/不存在可卡因/儿茶酚胺的情况下HIV感染的淋巴样细胞是否诱导潜伏的CMV感染的自体主动脉内皮细胞的潜伏期破裂e)确定在单独存在可卡因/儿茶酚胺的情况下MVEC和自体平滑肌细胞（SMC）的共培养HIV/SIV感染的自体细胞单独或联合导致SMC增殖和重塑，f)确定HIV-1/SIV感染的细胞单独和/或存在可卡因/儿茶酚胺的相互作用是否导致金属蛋白酶的合成。我们认为，这些研究可能为可卡因和艾滋病毒感染在心血管疾病发病机制中的作用之间的关系提供独特的见解。

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.