MECHANISMS OF LIPODYSTROPHY IN HIV INFECTED PATIENTS

人类免疫缺陷病毒（HIV）感染是一个重大的全球性健康问题。 最近，包括HIV-1蛋白酶抑制剂（PI）在内的联合治疗显著提高了HIV（+）患者的长期生存率。 然而，这种治疗与脂肪营养不良综合征相关，其特征在于面部和四肢的皮下（sc）脂肪显著减少，但颈部、颈背部和躯干周围的sc脂肪过量。这些患者具有增加的胰岛素抵抗、糖尿病和血脂异常的倾向。 HIV感染患者脂肪代谢障碍综合征的代谢和分子基础尚不清楚。 除PI外，其他抗逆转录病毒药物、HIV感染和病毒载量减少是否有助于脂肪代谢障碍综合征的发展尚不清楚。 因此，该项目有以下目标：1）确定代谢异常和体脂分布变化的特征，2）制定定义综合征的客观标准并确定预后指标，3）阐明艾滋病毒感染患者脂肪代谢障碍综合征的分子基础。 为了实现这些目标，我们将在200例无症状HIV（+）患者中进行一项为期2年的前瞻性、随机、双盲、安慰剂对照研究，以比较两种同样有效的抗逆转录病毒方案，一种有PI，另一种没有PI。 我们将通过人体测量和磁共振成像研究体脂分布，并测量胰岛素敏感性（在一部分患者中）、血浆脂蛋白、葡萄糖耐量和其他代谢变量。 我们将研究一系列脂肪细胞特异性蛋白质/转录因子的表达，这些蛋白质/转录因子参与脂肪细胞分化、胰岛素作用和治疗前后脂肪活检样本中的脂蛋白代谢。 确定HIV（+）患者脂肪代谢障碍综合征的代谢和分子基础，可能有助于更好地理解脂肪细胞特异性基因在胰岛素作用和体脂分布中的作用，并可能发现其他不会引起脂肪代谢障碍综合征的抗逆转录病毒药物。 此外，该研究可能证明无PI的替代抗逆转录病毒方案的有效性和降低的毒性。

Human immunodeficiency virus (HIV) infection is a major global health problem. Recently, combination therapy including HIV-1 protease inhibitors (PIs) has dramatically improved the long-term survival of HIV (+) patients. However, such therapy is associated with a lipodystrophy syndrome characterized by marked loss of subcutaneous (sc) fat from the face and extremities but excess of sc fat around the neck, dorsocervical region and trunk. Such patients have increased propensity to insulin resistance, diabetes mellitus and dyslipidemia. The metabolic and molecular basis of lipodystrophy syndrome in HIV-infected patients is not known. Whether besides PIs, other antiretroviral drugs, HIV infection and reduction in viral load contribute to the development of lipodystrophy syndrome is not clear. The project therefore has the following aims: 1) to characterize metabolic abnormalities and changes in body fat distribution, 2) to develop objective criteria for defining the syndrome and to ascertain prognostic indicators and 3) to elucidate the molecular basis of the lipodystrophy syndrome in HIV-infected patients. To accomplish these aims, we will conduct a 2-year long prospective, randomized, double blind, placebo-controlled study in 200 asymptomatic HIV (+) patients to compare two equally effective antiretroviral regimens, one with and the other without a PI. We will study body fat distribution by anthropometry and magnetic resonance imaging and will measure insulin sensitivity (in a subset of patients), plasma lipoproteins, glucose tolerance and other metabolic variables. We will study expression of an array of adipocyte specific proteins/transcription factors involved in adipocyte differentiation, insulin action and lipoprotein metabolism in fat biopsy samples obtained before and after institution of therapy. Identification of the metabolic and molecular basis of lipodystrophy syndrome in HIV (+) patients may lead to better understanding of role of adipocyte-specific genes in insulin action and body fat distribution and may lead to discovery of other antiretroviral drugs that do not cause the lipodystrophy syndrome. Additionally, the study may prove effectiveness and reduced toxicity of alternative antiretroviral regimens without a PI.