Evolution of resistance to HIV-1 reverse transcriptase inhibitors

The human immunodeficiency virus (HIV) is the primary etiologic agent of the acquired immunodeficiency syndrome (AIDS). HIV replicates as a complex and dynamic population of mutants referred to as viral quasispecies, which can be seen as a cloud of distinct but closely related genetic variants. The selection of drug-resistant HIV variants from the quasispecies and the transmission of these resistant viruses to new individuals are of major concern in the treatment of HIV-infected individuals. In this thesis we have investigated which factors drive the evolution of resistance to the class of HIV-1 reverse transcriptase inhibitors (RTIs) in the absence and presence of drugs. First, we have studied which factors influence the genetic barrier to resistance, which is defined as the difficulty for HIV-1 to escape antiretroviral drug pressure. The interplay between resistance-associated mutations and the presence of minority variants before start of treatment seem to influence the genetic barrier to resistance, which might lead to early virological failure on specific regimens. We have also shown that after twenty years of treatment of HIV-1 infections the complete resistance patterns to RTIs are not fully elucidated yet. Novel amino acid changes have been identified that are able to further increase the level of drug resistance. In general, these mutations have shown to result in a decrease in the intrinsic viral replication capacity in the absence of treatment. However, we have demonstrated that HIV-1 is also able to select mutations that are capable of increasing the replication capacity of these resistant variants. For the treatment of infected individuals it is important to determine the clinical importance of these amino acid changes. Also, the identification of these novel amino acid changes that affect resistance and/or replication capacity clearly underscores the need for novel antiretroviral drugs. Furthermore, we have demonstrated that some of these compensatory mutations are responsible for the fixation of a resistance mutation in the absence of drugs. The presence of these compensatory amino acid changes resulted in an increase in replication capacity of the resistance-associated variants and could explain the persistence for prolonged periods of replication in the absence of therapy. The selection and frequent transmission of such compensated resistant viruses seems worrisome and the introduction of such viruses in the population should be prevented. Considering the decreased genetic barrier to resistance of such viruses, the treatment options might be limited for these infected individuals