The effects of HIV-1 proteins on adipocyte biology

描述（由申请人提供）：强效抗逆转录病毒疗法已经实现了提高HIV感染患者生存率的承诺。然而，有效的抗逆转录病毒治疗与身体脂肪再分配和代谢紊乱有关，包括胰岛素抵抗和动脉粥样硬化性血脂异常。与抗逆转录病毒治疗相关的体脂变化包括内脏脂肪的积累以及四肢和面部皮下脂肪的消耗。这些身体脂肪的变化会给受影响的患者带来情绪和身体上的困扰，并可能在HIV脂肪营养不良的代谢紊乱中发挥作用。这些患者所经历的代谢紊乱引起了人们的担忧，即许多患者将继续发展为糖尿病和动脉粥样硬化性心脏病。此外，由于这些问题，抗逆转录病毒治疗的依从性可能受到影响。因此，必须制定策略，预防和治疗与强效抗逆转录病毒治疗相关的代谢紊乱和体脂变化。只有当人们更好地了解hiv感染患者中常见的身体脂肪变化的发病机制时，才能做到这一点。除了队列研究外，HIV感染本身在这种脂肪营养不良综合征中的作用尚未得到研究。因此，我们建议研究HW-1蛋白和gp-120在使用和不使用抗逆转录病毒药物时对脂肪细胞生物学的影响。此外，目前尚不清楚为什么抗逆转录病毒治疗后皮下脂肪储备减少，而内脏脂肪储备不受影响或增加。我们建议确定抗逆转录病毒药物和/或HIV-1蛋白对人类皮下和内脏脂肪细胞的前期和成熟脂肪细胞是否有不同的影响。换句话说，内脏储藏库必须以某种方式抵抗抗逆转录病毒药物和/或艾滋病毒感染本身的作用。最后，皮下脂肪组织库的脂肪消耗在接受强效抗逆转录病毒治疗的患者中极为常见。然而，目前还没有前瞻性研究来确定抗逆转录病毒治疗如何改变这一基因表达。这种方法可以为HIV脂肪营养不良综合征的发病机制提供重要的见解。这些新的研究应该为进一步了解与HIV脂肪营养不良综合征相关的体脂变化的发病机制提供帮助。

DESCRIPTION (provided by applicant): Potent antiretroviral therapy has fulfilled its promise to improve survival in patients with HIV infection. However, potent antiretroviral therapy is associated with body fat redistribution and metabolic derangements including insulin resistance and an atherogenic dyslipidemia. The body fat changes associated with antiretroviral therapy include accumulation of visceral fat and wasting of the subcutaneous fat of the extremities and face. These body fat changes cause emotional and physical distress for affected patients and may play a role in the metabolic disturbances of HIV lipodystrophy. The metabolic derangements experienced by these patients raise concerns that many patients will go on to develop diabetes and atherosclerotic heart disease. In addition, compliance with antiretroviral therapy may be affected because of these problems. It is therefore essential to develop strategies to both prevent and treat the metabolic disturbances and body fat changes associated with potent antiretroviral therapy. This can be done only when the pathogenesis of the body fat changes now so common in HIV-infected patients is better understood. Except for cohort studies, the role of HIV infection itself in this lipodystrophy syndrome has not been studied. We therefore propose to study the effects of the HW-1 proteins tat and gp-120 with and without antiretroviral agents on adipocyte biology. In addition, it is not understood why the subcutaneous fat depot decreases on antiretroviral therapy but the visceral depot is unaffected or grows. We propose to determine if there are differential effects of antiretroviral agents and/or HIV-1 proteins on pre- and mature adipocytes from the subcutaneous and visceral depots of humans. In other words, the visceral depot must be in some way resistant to the effects of the antiretroviral agents and/or HIV infection itself. Finally, fat wasting of the subcutaneous adipose tissue depot is extremely common in patients on potent antiretroviral therapy. However, no prospective studies have been done to determine how gene expression in this depot is altered by initiation of antiretroviral therapy. This approach could provide important insights into the pathogeneis of this troubling aspect of the HIV lipodystrophy syndrome. These novel studies should provide further insight into the pathogenesis of the body fat changes associated with the HIV lipodystrophy syndrome.