Mechanisms of resistance associated with excision of incorporated nucleotide analogue inhibitors of HIV-1 reverse transcriptase.
OBJECTIVE
Nucleoside analogue reverse transcriptase inhibitors are important components in current drug regimens used to treat infection with HIV. Despite the potency of drug combinations that involve two nucleoside reverse transcriptase inhibitors and a non-nucleoside analogue or a protease inhibitor, the emergence of resistance remains a major reason for treatment failure. This article reviews biochemical mechanisms associated with resistance to nucleoside reverse transcriptase inhibitors.


RESULTS
The thymidine analogues zidovudine and stavudine select for mutational patterns that facilitate the phosphorolytic excision of literally all available nucleoside reverse transcriptase inhibitors. Major progress has been made in defining genotypes that either support or counteract the reaction. Thymidine analogue-associated mutations were shown to increase rates of excision. In contrast, non-thymidine analogue reverse transcriptase inhibitors select for different mutations, e.g. M184V, L74V, and K65R that diminish the effects of thymidine analogue-associated mutations. Possible underlying biochemical mechanisms are discussed in this review.


CONCLUSIONS
The non-thymidine analogue-associated mutations M184V, L74V, and K65R show incompatibilities with thymidine-analogue-associated mutations. Maximizing these effects in clinical practice may help delay the emergence of resistance. Together, the clinical and biochemical data validate the excision reaction as a target for the development of novel compounds that interfere with the reaction.
McGill University, Department of Microbiology and Immunology, Montreal, Quebec, Canada H3A 2B4. matthias.gotte@mcgill.ca
Matthias
M
Götte