Each of the 14 approved antiretroviral drugs belongs to one of three classes: nucleoside reverse transcriptase (RT) inhibitors (NRTI), nonnucleoside RT inhibitors (NNRTI), and protease inhibitors (PI). Within each drug class, there is extensive cross-resistance. Many of the mutations that develop in HIV-1 isolates from patients treated with one drug confer cross-resistance to other drugs of the same drug class. For example, K103N causes high-level resistance to the three available NNRTI, L90M causes some degree of resistance to the four available protease inhibitors, and Q151M confers resistance to each of the NRTI except 3TC.

Drug resistance mutations can be synergistic in that their accumulation within RT or protease will lead to increased levels of drug resistance or extend the spectrum of resistance to include additional drugs. Drug resistance mutations can also be antagonistic. When this occurs, one mutation will decrease drug resistance caused by another mutation. The two most noteworthy examples of mutation antagonism are the suppression of T215Y-mediated AZT resistance by the ddI resistance mutation L74V and the 3TC resistance mutation M184V (Figures 1 and 2) [1,2].

Antagonistic interactions between mutations are more than just interesting laboratory observations. In patients receiving AZT + 3TC, HIV-1 isolates develop M184V and become resistant to 3TC, but AZT resistance is delayed. In patients receiving AZT + ddI, HIV-1 isolates develop T215Y and AZT resistance, but L74V is prevented and ddI resistance is delayed (2,3). Dual nucleoside resistance can develop but generally requires the accumulation of multiple additional mutations [3].

The higher genetic barrier to drug resistance posed by certain dual nucleoside combinations probably accounts for the clinical benefits of the most commonly used dual nucleoside combinations: AZT + 3TC, AZT + ddI, d4T + 3TC, and d4T + ddI. Each of these combinations provides durable HIV-1 suppression when used in combination with either a PI or NNRTI. (I include d4T + 3TC and d4T + ddI because the genetic mechanisms of resistance to AZT and d4T appear to be similar [4].)

Other antagonistic interactions between HIV-1 drug resistance mutations have been identified, but unlike 184/215 and 74/215, these interactions have not had clinical applications. However, as long as the number of HIV-1 treatment targets remains limited, it will be critical to determine whether combinations of resistance mutations are synergistic or antagonistic. When antagonistic mutations are identified, drug combinations that exploit this antagonism should be considered in designing highly active antiretroviral treatment regimens.