Dysregulation of lipid metabolism is a common feature of HIV infection. It is most often observed in patients treated with protease inhibitors, but has been also described as a side effect of other classes of anti-HIV drugs. Abnormalities in lipid metabolism put HIV-infected patients at high risk for developing atherosclerosis and heart disease. Therefore, studies of lipid regulation should accompany development of new anti-HIV compounds. Unfortunately, mechanisms responsible for atherogenic effect of anti-HIV drugs are not understood. Based on similarities in lipid abnormalities between AIDS patients and patients with type II diabetes, where defects of reverse cholesterol transport were found to play a major pathogenic role in lipid dysregulation, and on our preliminary results that show suppression of cholesterol efflux by HIV infection, we hypothesize that a similar mechanism applies to HIV-infected individuals. To test this hypothesis and to analyze the effect on reverse cholesterol transport of anti-HIV compounds under investigation in the project funded by the parent grant, we propose the following Specific Aims:
Specific Aim 1. To investigate the effect of HIV infection and anti-HIV compounds on rates of individual steps of reverse cholesterol transport in vitro.
Specific Aim 2. To investigate the effects of HIV-1 infection and treatment with protease inhibitors on the status of reverse cholesterol transport in HIV-infected patients. The proposed studies address important research questions highly relevant to the goals of the parental grant. The knowledge obtained from this research would allow to improve AIDS therapy by suggesting targets for therapeutic treatment of lipid dysregulation and providing means for choosing compounds that lack this serious side-effect. The proposed collaboration provides a unique opportunity to perform such studies. The Australian collaborator, Dr. D. Sviridov, is a recognized expert with impressive track record in cholesterol transport and atherosclerosis. This research will be done primarily in Australia as an extension of the NIH grant #R01 AI 40386. ? ?
| Crowe, Suzanne M; Westhorpe, Clare L V; Mukhamedova, Nigora et al. (2010) The macrophage: the intersection between HIV infection and atherosclerosis. J Leukoc Biol 87:589-98 |
| Rose, Honor; Hoy, Jennifer; Woolley, Ian et al. (2008) HIV infection and high density lipoprotein metabolism. Atherosclerosis 199:79-86 |
| Mujawar, Zahedi; Rose, Honor; Morrow, Matthew P et al. (2006) Human immunodeficiency virus impairs reverse cholesterol transport from macrophages. PLoS Biol 4:e365 |
