Study Sheds Light on Cause of an AIDS Treatment Side Effect

Highly active antiretroviral therapy (HAART) has been associated with the development of lipodystrophy syndromes. Lipodystrophy, a clinical condition characterized by poor or uneven distribution of fat cells, can lead to lower belly obesity and a hump on the upper back. Lipodystrophy side effects also include diabetes and high levels of cholesterol and triglycerides.

In a test-tube study published in Mitochondrion (September 2002), researchers from the National Cancer Institute, the National Institute of Standards and Technology, and Purdue University report that protease inhibitors, a component of HAART, can lead to mitochondrial toxicity. The clinical features of HAART-associated lipodystrophy are similar to those seen in people with mitochondrial dysfunction. The powerhouse of the cell, the mitochondrion processes proteins and produces energy. Interference with its normal activity can lead to distortion or dysfunction of other cellular processes.

Researchers have long known that the nucleoside-analogue reverse transcriptase inhibitors (NRTIs) in HAART cocktail regimens can cause mitochondrial toxicity by inhibiting a mitochondrial enzyme called DNA polymerase gamma. The current study shows that protease inhibitors can directly affect the enzyme mitochondrial processing protease (MPP), thus leading to mitochondrial dysfunction that might contribute to the development of lipodystrophy.

While protease inhibitors alone do not necessarily cause lipodystrophy, the combined direct effects on mitochondria of protease inhibitors and NRTIs can possibly lead to the condition. In addition, protease inhibitors are highly hydrophobic (water insoluble), and may concentrate in fatty tissues. The drugs would have a greater impact on mitochondria in tissues with chronic exposure.

"This finding that protease inhibitors affect MPP could be useful if one wants to develop inhibitors of MPP for other conditions, such as cancer," said Henry Weiner, Ph.D., of Purdue University.

The authors do not know to what degree MPP inhibition correlates with mitochondrial disruption, nor if their results with isolated mitchondria in the test tube study actually occur in patients. However, scientists have found that both NRTIs and protease inhibitors have direct effects on fat cells, and mitochondrial abnormalities in fat tissue have been found in patients with lipodystrophy. The researchers call for further study of MPPs and recommend that scientists designing new HIV/AIDS drugs attempt to minimize the drugs' adverse effects on mitochondria.

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