STRUCTURAL MECHANISMS OF HIV DRUG-RESISTANCE

Antiviral therapy for AIDS has focused on the discovery and design of inhibitors for two main enzyme targets of the human immunodeficiency v irus type 1 (HIV)-reverse transcriptase (RT) and protease (PR). Despit e several classes of promising new anti-HIV agents, the clinical emerg ence of drug-resistant variants of HIV has severely limited the long-t erm effectiveness of these drugs. Genetic analysis of resistant virus has identified a number of critical mutations in the RT and PR genes. Structural analysis of inhibitor-enzyme complexes and mutational model ing studies are leading to a better understanding of how these drug-re sistance mutations exert their effects at a structural level. These in sights have implications for the design of new drugs and therapeutic s trategies to combat drug resistance to AIDS.