Variants with different mutation patterns persist in the quasispecies of enfuvirtide-resistant HIV-1 population during and after treatment in vivo.
BACKGROUND
Genotypic and phenotypic resistance in 11 HIV-1-infected patients receiving enfuvirtide (ENF), as part of a salvage regimen, has been evaluated.


METHODS
Resistance mutations were detected by sequencing the gp41 ectodomain from plasma samples. During treatment, longitudinal samples from 1 patient were sequenced after limiting dilution of complementary DNA to isolate single genomes. Phenotypic resistance was evaluated with a new recombinant virus assay (PHENOSCRIPT; VIRalliance, Paris, France), allowing the determination of coreceptor use.


RESULTS
All patients experienced ENF failure. One to 4 mutations in the 36-to-45 gp41 region appeared during ENF therapy in all patients and disappeared after ENF removal. Mixtures of wild type and mutants unexpectedly persisted under ENF treatment, however, despite continued replication, leading to discordant results between genotypic and phenotypic data. Sequencing of isolated genomes from 1 patient confirmed that a wild-type first heptad repeat region (HR1) region was still present at the end of therapy. Several mutated variants coexisted at different time points, despite a tendency toward quasispecies reduction with time.


CONCLUSIONS
Individual variability of the mutation pattern and persistence of strains without mutation in the region mainly targeted by ENF resistance probably reflect the fact that resistance to ENF may rely on regions of gp41 or gp120 other than residues 36 to 45.
Trabaud
Mary Anne
MA
Virology Laboratory, Croix Rousse Hospital, Lyon, France. mary-anne.trabaud01@chu-lyon.fr
Cotte
Laurent
L
Labernardière
Jean Louis
JL
Lebel-Binay
Sophie
S
Icard
Vinca
V
Tardy
Jean-Claude
JC
Trepo
Christian
C
Andre
Patrice
P
D000595:Amino Acid Sequence; D024882:Drug Resistance, Viral / Q000235:genetics; D000077560:Enfuvirtide; D014644:Genetic Variation; D015700:HIV Envelope Protein gp41 / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology* / Q000627:therapeutic use; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D010446:Peptide Fragments / Q000494:pharmacology* / Q000627:therapeutic use; D010802:Phylogeny; D017434:Protein Structure, Tertiary / Q000235:genetics; D012189:Retrospective Studies; D016415:Sequence Alignment; D017211:Treatment Failure; D019562:Viral Load
D015700:HIV Envelope Protein gp41; D010446:Peptide Fragments; C514787:gp41 protein, Human immunodeficiency virus 1; D000077560:Enfuvirtide