title: Evolution of tenofovir-resistant HIV-1 isolates exposed to tenofovir alafenamide dose escalation.
abstract: Resistance selection experiments using HIV-1 isolates harboring pre-existing tenofovir (TFV)-resistance (K65R, 3TAMs, and Q151M complex) were carried out with the novel tenofovir prodrug tenofovir alafenamide (TAF) as well as with tenofovir (TFV), to investigate the potential for additional resistance development in the presence of TAF or TFV. Extended resistance selection of these TFV resistance associated mutations (RAMs)-containing viruses with TAF or TFV did not lead to the accumulation of additional known RAMs, or significant additional phenotypic resistance, after 6 months in culture. Two new mutations were found during the selections (L429I, T69I) that were further characterized, and found to have very limited or no role in resistance to TAF or TFV. Notably, viral survival in the presence of drug increases could not be sustained and led to viral cure in cell culture, suggesting a lack of alternative resistance pathways for the mutant viruses.
authors.affiliation: Clinical Virology, Gilead Sciences, Inc., Foster City, CA, USA. Electronic address: stephanie.cox@gilead.com.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Cox
authors.affiliation: Clinical Virology, Gilead Sciences, Inc., Foster City, CA, USA.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Margot
authors.affiliation: Clinical Virology, Gilead Sciences, Inc., Foster City, CA, USA.
authors.forename: Renee
authors.initials: R
authors.lastname: Ram
authors.affiliation: Clinical Virology, Gilead Sciences, Inc., Foster City, CA, USA.
authors.forename: Audun
authors.initials: A
authors.lastname: Johnson
authors.affiliation: Clinical Virology, Gilead Sciences, Inc., Foster City, CA, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Miller
authors.affiliation: Clinical Virology, Gilead Sciences, Inc., Foster City, CA, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Callebaut
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000409:Alanine; D019380:Anti-HIV Agents / Q000494:pharmacology*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D024882:Drug Resistance, Viral / Q000235:genetics*; D019143:Evolution, Molecular; D005838:Genotype; D057809:HEK293 Cells; D015658:HIV Infections / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008826:Microbial Sensitivity Tests; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D010641:Phenotype; D011355:Prodrugs; D011995:Recombination, Genetic; D000068698:Tenofovir / Q000494:pharmacology* / Q000031:analogs & derivatives
chemical_list: D019380:Anti-HIV Agents; D011355:Prodrugs; D000068698:Tenofovir; C442442:tenofovir alafenamide; D000225:Adenine; D000409:Alanine