HIV protease inhibitors: antiretroviral agents with anti-inflammatory, anti-angiogenic and anti-tumour activity.

Despite mild toxicity and adverse effects, human immuno- deficiency virus (HIV) protease inhibitors (PIs), used in combination with reverse transcriptase nucleoside inhibitors (NRTIs), have turned AIDS into a chronic, manageable disease. Such combination therapy, known as highly active antiretroviral therapy (HAART), efficiently suppresses HIV replication leading to immune restoration in HIV-infected patients. HIV PIs act by blocking the HIV aspartyl protease, a viral enzyme that cleaves the HIV gag and gag-pol poly- protein backbone at nine specific cleavage sites to produce shorter, functional proteins. Three of the nine cleavage reactions occur between a phenylalanine or a tyrosine and a proline. Strikingly, none of the known mammalian endo- peptidases cleaves before a proline; for this reason, most HIV PIs have been designed to mimic the phenylalanine-proline peptide bond. This confers a remarkable specificity of action to HIV PIs and, with short-term treatment, they show only mild side-effects and a tolerable toxicity. 1 Unexpectedly, however, the long-term treatment of re- sponder patients with PI-containing HAART has been shown to be associated with several unpredicted effects, such as hyper- bilirubinaemia, insulin resistance, hyper- or hypo-lipidaemia, fat body redistribution, osteopenia and osteoporosis. 2 A reduced incidence and an increased regression of AIDS- associated tumours including Kaposi's sarcoma (KS) and some types of non-Hodgkin lymphomas (NHLs), namely cerebral and immunoblastic lymphomas, have been described since the introduction of PI-HAART compared with the pre- HAART era. 3-7 The exact mechanism(s) of these effects,