Abstract
One of the most promising targets in the development of an anti-viral therapy against the AIDS virus has been the protease (HIV-1 PR) that the HIV virus uses for the cleavage of the gag and gag-pol complex during viral replication.1 Many research laboratories have developed HIV-1 PR inhibitors that have become lead compounds for anti-viral drugs. Some of these compounds have been found to stop very effectively the replication of the HIV-1 virus in vitro.2–4 However they seem to have limited clinical benefit, due in part to the development of viral resistance. The HIV virus is able to generate drug resistance because of the high mutational frequency in the replication of its genome. Under the ‘evolutionary pressure’ from an anti-viral agent a drug resistant mutant is selected. The primary sequence modifications that are generated in this way are called ‘resistance’ mutations and have been observed in vitro 5–9 and in vivo.10,11 They maintain the level of catalytic activity, allowing the virus to replicate, but they lower the affinity of the HIV-1 PR for the anti-viral drug, reducing the drug’s potential therapeutic power. At present, the molecular mechanisms that underlie drug resistance are not fully understood. Their elucidation will represent a step towards the formulation of novel drugs that could overcome this hurdle.
Published Version
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