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Genotype and phenotype patterns of human immunodeficiency virus type 1 resistance to enfuvirtide during long-term treatment
- Source :
- Antimicrobial agents and chemotherapy. 48(9)
- Publication Year :
- 2004
-
Abstract
- The human immunodeficiency virus type 1 (HIV-1) fusion inhibitor enfuvirtide has recently been introduced into clinical practice and has exhibited efficient anti-HIV-1 activity in combination with other antiretroviral agents. In the present study, we addressed the effect of long-term treatment with enfuvirtide on the intrahost evolution of HIV-1. The genotype and phenotype patterns and the relative replication capacity (rRC) of enfuvirtide-resistant HIV-1 mutants were evaluated in samples from 11 subjects (7 virological nonresponders and 4 responders) who received the compound for more than 1 year in combination with different regimens. Selection of one or more mutations clustering in a sequence (amino acids 36 to 45) of the gp41 N-terminal heptad repeat was observed in samples from the seven virological nonresponders but not in those from responders. In two subjects who discontinued enfuvirtide, reversion of the resistant genotype was detected within 3 months. Recombinant clones bearing mutated gp41 sequences displayed reduced susceptibilities to enfuvirtide, with the 50% inhibitory concentrations (IC 50 s) ranging from 0.6 to 12.8 μg/ml, whereas the IC 50 for isolates with baseline sequences was 0.013 ± 0.010 μg/ml. Interestingly, long-term monitoring of resistant variants provided evidence that ongoing adaptation to the drug is paralleled by phenotypic changes. A limited drop in the rRC in the absence of drug was observed for clones from four of the seven nonresponders bearing mutations associated with resistance. Overall, the data indicate that the different genotype patterns associated with a detectable degree of HIV-1 resistance to enfuvirtide generated during long-term treatments are characterized by a substantially low genetic barrier, possible ongoing adaptation with increased degrees of resistance, and limited influence on the viral rRC.
- Subjects :
- Enfuvirtide
Genotype
Molecular Sequence Data
Reversion
HIV Infections
Gp41
Virus Replication
Antiviral Agents
Virus
Genotype-phenotype distinction
HIV Fusion Inhibitors
Drug Resistance, Viral
medicine
Humans
Pharmacology (medical)
Amino Acid Sequence
Cloning, Molecular
Pharmacology
biology
biology.organism_classification
Phenotype
Virology
Long-Term Care
HIV Envelope Protein gp41
Peptide Fragments
CD4 Lymphocyte Count
Infectious Diseases
Lentivirus
Immunology
Mutation
HIV-1
medicine.drug
Subjects
Details
- ISSN :
- 00664804
- Volume :
- 48
- Issue :
- 9
- Database :
- OpenAIRE
- Journal :
- Antimicrobial agents and chemotherapy
- Accession number :
- edsair.doi.dedup.....a27b00cce5e88dd709b1170d3972bbb1