Centre national de la recherche scientifique et Universités d'Aix-Marseille I et II, UMR 6098, Architecture et fonction des macromolécules biologiques, ESIL-Case 925, 163, avenue de Luminy, 13288 Marseille Cedex 9
Nucleosides analogues play a key role in the antiretroviral chemotherapy. After intracellular activation to the 5'-triphosphate form, they act as specific terminators of the viral DNA synthesis by reverse transcriptase. Under therapeutic pressure, the viral reverse transcriptase gene mutates and specifies enzymes bearing substitutions responsible for the loss of efficacy of the nucleoside analogue. It is not usually easy to detect, understand, and quantify nucleoside analogue resistance using purified reverse transcriptase and biochemical assays. This work is an overview of the main biochemical assays used to study RT-mediated resistance due to either nucleotide analogue discrimination or repair of the analogue-terminated DNA chain. Understanding the molecular basis of drug-resistance is essential for a rational combination of drugs, and for the design of drugs which either do not select resistance or target drug-resistant viruses.