Abstract
BackgroundCombination anti-viral therapies have reduced treatment failure rates by requiring multiple specific mutations to be selected on the same viral genome to impart high-level drug resistance. To determine if the common protease inhibitor resistance mutation L90M is only selected once or repeatedly on different HIV genetic backbones during the course of failed anti-viral therapies we analyzed a linked region of the viral genome during the evolution of multi-drug resistance.ResultsUsing L90M allele specific PCR we amplified and sequenced gag-pro regions linked to very early L90M containing HIV variants prior to their emergence and detection as dominant viruses in 15 failed salvage therapy patients. The early minority L90M linked sequences were then compared to those of the later L90M viruses that came to dominate the plasma quasispecies. Using Bayesian evolutionary analysis sampling trees the emergence of L90M containing viruses was seen to take place on multiple occasion in 5 patients, only once for 2 patients and an undetermined number of time for the remaining 8 patients.ConclusionThese results indicate that early L90M mutants can frequently be displaced by viruses carrying independently selected L90M mutations rather than by descendents of the earlier mutants.
Highlights
High rates of human immunodeficiency virus (HIV) replication and mutation in vivo results in the continuous generation of genetic variation [1]
Primary drug resistance mutations that alone confers moderate resistance such as V82A and L90M are initially selected followed by the addition of secondary mutations often located outside of the active site of the PR, such as L10I, M36I, M46I, L63P, or A71V leading to higher levels of resistance [9,10]
Selective amplification of variant carrying L90M mutation PCR primers were designed and tested to amplify variants carrying the protease drug resistance mutation L90M present at low frequencies within quasispecies dominated by wild type viruses
Summary
High rates of human immunodeficiency virus (HIV) replication and mutation in vivo results in the continuous generation of genetic variation [1]. Different amino acid substitutions in the viral protease region are tightly associated with reduced sensitivity to protease inhibitors and rebounding viral loads. These mutations may emerge in a sequential order [58]. Combination anti-viral therapies have reduced treatment failure rates by requiring multiple specific mutations to be selected on the same viral genome to impart high-level drug resistance. To determine if the common protease inhibitor resistance mutation L90M is only selected once or repeatedly on different HIV genetic backbones during the course of failed antiviral therapies we analyzed a linked region of the viral genome during the evolution of multi-drug resistance
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