We previously described the emergence of a drug-dependent HIV-1 variant in a patient on T20 (enfuvirtide) therapy . This variant first acquired a resistance mutation in the T20-binding site of the envelope (Env) protein that provided resistance to the inhibitor, but at a fitness cost. The virus then evolved further to repair this fitness defect by introducing a second-site compensatory mutation in the Env protein. This evolution event took place in the presence of the inhibitor, which became critically involved in the mechanism of Env-mediated membrane fusion. This resulted in a virus variant with improved fitness that was both resistant and critically dependent on the inhibitor for its replication.
There have been several in vitro reports on the selection of partially and fully drug-dependent HIV-1 variants to a number of antiviral compounds that target different steps in the virus life cycle. We will argue that, in many cases, the evolution of the drug-dependence phenomenon occurs via a similar path: the selection of initial drug-resistance mutations that reduce the fitness of the virus, and subsequently the introduction of second-site compensatory mutations that evolve in the presence of inhibitor to improve the fitness of the virus. This scenario may result in a better replicating virus variant that mechanistically uses the inhibitor and such a variant will show severely reduced fitness when the inhibitor is removed from the environment.
The evolution of drug-dependence may depend on the mechanistic nature of the inhibitor. For example, inhibitors that mimic a certain sequence or domain of the virus such as the fusion inhibitor T20 may be more prone to select for drug-dependent viruses as the mimicking peptide is able to become involved in the mechanistic process of Env-mediated membrane fusion. As discussed in more detail below, protease resistant HIV-1 variants could also adapt and optimize protease activity in the presence of a protease inhibitor , but no such phenomenon has been reported thusfar for reverse transcriptase inhibitors. We will review all studies that report drug-enhanced or drug-dependent HIV-1 variants. There is a growing body of evidence to suggest that drug-dependence is a more common phenomenon. In many cases, drug-dependence will be missed because the virus does not replicate without the drug, which is usually an indication for the researcher to stop any further experimentation. Furthermore, a drug-dependence phenotype will easily be missed in the diagnostic resistance screening assays used today such as the MTT assay.