Background:  Nucleoside/nucleotide (NRTI) and non-nucleoside reverse transcriptase inhibitors (NNRTI) are integral components of therapy for HIV-1 infection.  Although combination therapies that contain two or more RTI have profoundly reduced morbidity and mortality from HIV-1 infection, their long-term efficacy is limited by the selection of drug-resistant variants of HIV-1. An in-depth understanding of RTI resistance is needed to prevent and manage resistance effectively.

Methods:  Using a multi-disciplinary approach that includes molecular virology, biochemistry and structural biology, several groups, including ours, have begun to define and characterize the mechanisms of RTI resistance and interactions that impact treatment response.

Results:  NRTI-associated resistance mutations can be broadly categorized into 2 groups depending on their phenotypic mechanism of resistance. Thymidine analog mutations (TAM), such as M41L, D67N, K70R, and T215F/Y, augment the ability of HIV-1 RT to excise the chain-terminating NRTI-monophosphate from a prematurely terminated DNA chain. In comparison, mutations such as K65R, K70E, L74V, and M184V increase the selectivity of RT for incorporation of the natural dNTP substrate versus the NRTI-triphosphate. In many instances, NRTI resistance mutations are antagonistic toward one another, and this antagonism can be exploited clinically. NNRTI-associated mutations confer resistance by preventing the inhibitor from binding at the NNRTI-binding pocket. Interestingly, some NNRTI resistance mutations, such as Y181C, are also antagonistic toward TAM.

Conclusions:  By understanding the mechanisms of RTI resistance and the interactions between resistance mutations, appropriate RTI drug combinations can be formulated that provide sustained clinical benefit.