The biochemical basis for the development of lipodystrophy in HIV-1-infected patients treated with retroviral protease inhibitors (PIs) is unclear. Liang et al. 1 demonstrate that the PIs ritonavir and saquinavir affect fat metabolism through alterations in neutral lipid synthesis and the secretion of apolipoprotein B (ApoB). The authors also propose that inhibition of proteasomal chymotryptic activity by ritonavir and saquinavir contributes to the observed intracellular accumulation of ApoB in vitro. Whereas the latter effect requires drug concentrations in the region of 50–100 μM, the former effects occur at 5–15 μM. For several reasons, we question the relevance of effects on proteasome function to the development of metabolic abnormalities associated with PI-induced lipodystrophy in vivo.

First, although we agree that ritonavir and saquinavir inhibit the chymotryptic activity of isolated 20S proteasomes in vitro, two other HIV-1 PIs, indinavir and nelfinavir, do not 2, 3. The use of either indinavir or nelfinavir would therefore have provided relevant controls for the experiments attributing intracellular accumulation of ApoB to inhibition of proteasomal activity. Further, although ritonavir does seem particularly likely to induce severe dyslipidemia, this metabolic complication of therapy is a feature of all retroviral PIs. Thus, it is difficult to attribute PI-associated lipodystrophy primarily to proteasome inhibition.