HIV-protease inhibitors alter retinoic acid synthesis

Background: An increasing rate of highly-active antiretroviral therapy (HAART)-associated metabolic and morphological abnormalities has been reported in HIV-infected persons. Some of them resemble retinoid-related adverse events, indicating alteration(s) of retinol metabolism or of retinoic acid-mediated signalling. Objective: To evaluate retinol levels in patients with or without HAART and to assess the effect of antiretroviral agents on retinal dehydrogenase (RALDH), a key enzyme involved in retinoic acid synthesis. Design: Plasma retinol levels, measured in six patients receiving HAART and in five others with no antiretroviral therapy, were correlated with levels of serum retinol-binding proteins. We then studied the effects of seven antiretroviral agents on RALDH activity and gene expression in a kidney-derived cell line (LLCPK). Results: Plasma retinol levels in patients receiving HAART were decreased in comparison with those not receiving antiretroviral drugs (51 +/- 5 versus 66 +/- 11 mug/dl; P = 0.03), whereas retinol-binding protein levels were increased (68 +/- 18 versus 45 +/- 10 mg/l; P = 0.04). RALDH activity was heightened by ritonavir (24%), indinavir (17%), saquinavir (17%), zalcitabine (14%), delavirdine (12%) and nelfinavir (10%) and decreased (22%) by DMP-450. RALDH gene expression was induced only by indinavir. Conclusions: These data indicate that certain retinoid-like adverse effects in HAART-receiving patients are not due to higher retinol levels. Enhanced RALDH activity or/and gene expression by some protease inhibitors could increase retinoic acid concentrations. Elevated retinoic acid levels might be responsible for retinoid-like or other adverse effects due to alterations in the expression of retinoic acid-responsive genes. (C) 2001 Lippincott Williams & Wilkins.