Impact of the HIV-1 env Genetic Context outside HR1-HR2 on Resistance to the Fusion Inhibitor Enfuvirtide and Viral Infectivity in Clinical Isolates

Autor: Annemarie M. J. Wensing, Franky Baatz, Monique Nijhuis, Danielle Perez Bercoff, Martiene Riedijk, Herman G. Sprenger, Morgane Lemaire, Petra M. van Ham, Andy I. M. Hoepelman, Peter P. Koopmans, Jean-Yves Servais, Carole Devaux, Jean-Claude Schmit
Jazyk: angličtina
Rok vydání: 2011
Předmět:
Viral Diseases
Enfuvirtide
BASE-LINE SUSCEPTIBILITY
viruses
lcsh:Medicine
Protein Structure
Secondary
Immunodeficiency Viruses
HIV Fusion Inhibitors
Genotype
lcsh:Science
MAXIMUM-LIKELIHOOD
Phylogeny
Recombination
Genetic
Genetics
Infectivity
Multidisciplinary
env Gene Products
Human Immunodeficiency Virus
ENTRY INHIBITORS
ENVELOPE GLYCOPROTEIN
Antivirals
HIV Envelope Protein gp41
FUNCTIONAL-ROLE
Phenotype
Infectious Diseases
HUMAN-IMMUNODEFICIENCY-VIRUS
Medicine
Poverty-related infectious diseases Infectious diseases and international health [N4i 3]
Research Article
medicine.drug
Mechanisms of Resistance and Susceptibility
Context (language use)
Viral quasispecies
Biology
MEMBRANE-FUSION
Tropism
Microbiology
Viral Evolution
HEPTAD REPEAT
Inhibitory Concentration 50
Genetic Mutation
Virology
Drug Resistance
Viral
medicine
Humans
Base Sequence
Point mutation
lcsh:R
Virion
HIV
TYPE-1 GP41
Peptide Fragments
PHENOTYPIC RESISTANCE
HEK293 Cells
HIV-1
Microbial genetics
lcsh:Q
Zdroj: PLoS One, 6, 7
PLoS ONE, 6(7):21535. PUBLIC LIBRARY SCIENCE
PLoS One, 6
PLoS ONE, Vol 6, Iss 7, p e21535 (2011)
PLoS ONE
ISSN: 1932-6203
Popis: Contains fulltext : 95996.pdf (Publisher’s version ) (Open Access) Resistance mutations to the HIV-1 fusion inhibitor enfuvirtide emerge mainly within the drug's target region, HR1, and compensatory mutations have been described within HR2. The surrounding envelope (env) genetic context might also contribute to resistance, although to what extent and through which determinants remains elusive. To quantify the direct role of the env context in resistance to enfuvirtide and in viral infectivity, we compared enfuvirtide susceptibility and infectivity of recombinant viral pairs harboring the HR1-HR2 region or the full Env ectodomain of longitudinal env clones from 5 heavily treated patients failing enfuvirtide therapy. Prior to enfuvirtide treatment onset, no env carried known resistance mutations and full Env viruses were on average less susceptible than HR1-HR2 recombinants. All escape clones carried at least one of G36D, V38A, N42D and/or N43D/S in HR1, and accordingly, resistance increased 11- to 2800-fold relative to baseline. Resistance of full Env recombinant viruses was similar to resistance of their HR1-HR2 counterpart, indicating that HR1 and HR2 are the main contributors to resistance. Strictly X4 viruses were more resistant than strictly R5 viruses, while dual-tropic Envs featured similar resistance levels irrespective of the coreceptor expressed by the cell line used. Full Env recombinants from all patients gained infectivity under prolonged drug pressure; for HR1-HR2 viruses, infectivity remained steady for 3/5 patients, while for 2/5 patients, gains in infectivity paralleled those of the corresponding full Env recombinants, indicating that the env genetic context accounts mainly for infectivity adjustments. Phylogenetic analyses revealed that quasispecies selection is a step-wise process where selection of enfuvirtide resistance is a dominant factor early during therapy, while increased infectivity is the prominent driver under prolonged therapy.
Databáze: OpenAIRE
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