The effects of HIV-1 proteins on adipocyte biology

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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.