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阳性患者的长期存活率。然而，这种疗法与脂肪营养不良综合征有关，其特征是面部和四肢的皮下脂肪显著减少，但颈部、背颈区和躯干周围的皮下脂肪过剩。这些患者增加了胰岛素抵抗、糖尿病和血脂异常的倾向。HIV感染患者脂营养不良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、艾滋病毒感染和病毒载量的减少是否有助于脂肪营养不良综合征的发展尚不清楚。因此，该项目有以下目标：1)表征代谢异常和体内脂肪分布的变化，2)制定客观标准来定义综合征和确定预后指标，以及3)阐明艾滋病毒感染患者中脂营养不良综合征的分子基础。为了实现这些目标，我们将在200名无症状的HIV(+)患者中进行一项为期两年的前瞻性、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，一种使用PI，另一种不使用PI。我们将通过人体测量和磁共振成像研究身体脂肪分布，并将测量胰岛素敏感性(在部分患者中)、血浆脂蛋白、糖耐量和其他代谢变量。我们将研究一系列与脂肪细胞分化、胰岛素作用和脂蛋白代谢有关的脂肪细胞特异性蛋白/转录因子在治疗前后的脂肪活检样本中的表达。识别HIV(+)患者脂肪营养不良综合征的代谢和分子基础可能有助于更好地了解脂肪细胞特异性基因在胰岛素作用和体内脂肪分布中的作用，并可能导致发现其他不会导致脂肪营养不良综合征的抗逆转录病毒药物。此外，这项研究可能会证明没有PI的替代抗逆转录病毒方案的有效性和减毒作用。

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.