HIV Protease Inhibitors Impair Muscle Repair and Remodeling

The HIV protease inhibitors indinavir (Crixivan) and ritonavir (Norvir) impair myotube formation by reducing calpain activity, according to a report in the October issue of AIDS Research and Human Retroviruses.

Antiretroviral protease inhibitors have been implicated in muscle wasting, the authors explain, but the mechanism behind this effect is unknown.

Dr. Ralph J. Germinario from Lady Davis Institute for Medical Research in Montreal, and colleagues studied the effects of indinavir and ritonavir on the in vitro differentiation of two muscle cell lines.

Muscle cells treated with ritonavir had reduced calpain activity, the authors report. There was no change, however, in calpain protein levels. Calpain activity is thought to be crucial for myotube formation.

Myoblasts incubated with either indinavir or ritonavir did not develop multinucleated myotubes, the report indicates, even as late as day 6 of continued culture in fusion medium.

Cell viability and apoptosis were not influenced at the concentrations of protease inhibitor employed, the investigators note.

"The accumulated data indicate that the HIV protease inhibitors did not prevent the in vitro muscle-differentiation program, but inhibited myotube formation downstream of these major differentiation events, likely by reducing calpain activity," the researchers write.

"Our in vitro data suggest that the protease inhibitors present in HAART might contribute to the muscle wasting by reducing muscle repair and remodeling," the authors conclude. "Thus, whereas HAART reduces viral load and promotes well-being, we suggest that the protease inhibitor components of HAART are part of the mechanism initiating or maintaining wasting."

However, the investigators caution: "These results are preliminary and demonstrably linked to therapy-related calpain inhibition in vitro only. Therefore, considering any changes in currently accepted antiretroviral therapeutic regimens based on this report would be highly premature and inappropriate in the absence of additional evidence."

11/29/04

AIDS Res Hum Retroviruses 2004;20:1057-1062.