Persistence of HIV-1 variants with multiple protease inhibitor (PI)-resistance mutations in the absence of PI therapy can be explained by compensatory fixation.
OBJECTIVE
To investigate the mechanism explaining the persistence of human immunodeficiency virus (HIV) type 1 variants with multiple protease inhibitor (PI)-resistance mutations in the absence of PI therapy.


METHODS
Longitudinal genotypic analyses were performed on sequential samples obtained from 2 HIV-1-infected patients who had stopped PI therapy for 4 years. Replication capacity (RC) was determined using recombinant viruses. Subsequently, the effect that changing individual protease mutations back to wild type has on RC was analyzed.


RESULTS
We observed prolonged persistence (up to 4 years) of viruses with multiple protease mutations after PI therapy was stopped, despite the fact that the RC of the viruses was severely reduced. Forcing the virus to evolve toward wild type by changing individual protease mutations to wild type was unsuccessful, because all variants displayed a decreased RC in comparison with that of their predecessors.


CONCLUSIONS
We propose compensatory fixation as a mechanism for the in vivo persistence of variants with multiple PI-resistance mutations in the absence of PI therapy. Viruses with multiple PI mutations have (partially) compensated for the initial loss in RC. Therefore, reversion of a single mutation causes a (further) reduction in RC and, as a consequence, the route to wild type is blocked.
van Maarseveen
Noortje M
NM
Eijkman-Winkler Center, Department of Virology, University Medical Center Utrecht, Utrecht, The Netherlands.
Wensing
Annemarie M J
AM
de Jong
Dorien
D
Taconis
Maaike
M
Borleffs
Jan C C
JC
Boucher
Charles A B
CA
Nijhuis
Monique
M
D000595:Amino Acid Sequence; D045744:Cell Line, Tumor; D024921:Drug Resistance, Multiple, Viral / Q000235:genetics; D019143:Evolution, Molecular; D014644:Genetic Variation; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology*; D016333:HIV Protease / Q000235:genetics*; D017320:HIV Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use; D016415:Sequence Alignment; D014779:Virus Replication; D028761:Withholding Treatment
D017320:HIV Protease Inhibitors; D018894:Reverse Transcriptase Inhibitors; D016333:HIV Protease