title: HIV-2 antiviral potency and selection of drug resistance mutations by the integrase strand transfer inhibitor elvitegravir and NRTIs emtricitabine and tenofovir in vitro.
abstract: BACKGROUND
  HIV-2 is susceptible to only a subset of approved antiretroviral drugs. A single tablet regimen containing the integrase strand transfer inhibitor elvitegravir (EVG) boosted by cobicistat plus the nucleoside reverse transcriptase (RT) inhibitors emtricitabine (FTC) and tenofovir disoproxil fumarate (EVG/COBI/FTC/TDF) has potent activity against HIV-1 and may have utility against HIV-2.
  
  
  METHODS
  HIV-2 susceptibility to EVG, FTC, and tenofovir (TFV) and selection of resistance mutations were characterized in vitro using dose escalation and breakthrough methods. HIV-2 containing the selected mutations was constructed and phenotyped in vitro.
  
  
  RESULTS
  The inhibitors EVG, FTC, and TFV had potent activity against HIV-2 with EC50 values of 1.6 nM, 0.99 μM, and 3.5 μM, respectively. In resistance selections, EVG selected E92G/Q and S147N in integrase, FTC selected M184V/I in RT, and TFV selected K65R and Y115F in RT. HIV-2 site-directed mutant (SDM) viruses with E92G and E92Q integrase mutations showed 3.7- and 16-fold reduced susceptibilities to EVG, respectively. The RT M184I and M184V SDM viruses were both highly resistant to FTC (34- and >1000-fold, respectively). The RT K65R SDM virus had 2.2- and 9.1-fold reduced susceptibilities to TFV and FTC, respectively, and the addition of Y115F to K65R further decreased susceptibility to both drugs.
  
  
  CONCLUSIONS
  The antiretrovirals EVG, FTC, and TFV showed potent inhibition of HIV-1 and HIV-2 in vitro and selected analogous mutations in HIV-2 and HIV-1. This suggests that the single tablet regimen of EVG/COBI/FTC/TDF should be studied as a treatment option for HIV-2 infection and would likely select for known resistance mutations.
authors.affiliation: Department of Clinical Virology, Gilead Sciences, Inc, Foster City, CA.
authors.forename: Kristen
authors.initials: K
authors.lastname: Andreatta
authors.forename: Michael D
authors.initials: MD
authors.lastname: Miller
authors.forename: Kirsten L
authors.initials: KL
authors.lastname: White
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001483:Base Sequence; D017931:DNA Primers; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D024882:Drug Resistance, Viral / Q000235:genetics*; D000068679:Emtricitabine; D057809:HEK293 Cells; D019428:HIV Integrase Inhibitors / Q000494:pharmacology; D015498:HIV-2 / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D009154:Mutation; D063065:Organophosphonates / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D015363:Quinolones / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology; D000068698:Tenofovir
chemical_list: D017931:DNA Primers; D019428:HIV Integrase Inhibitors; D063065:Organophosphonates; D015363:Quinolones; D018894:Reverse Transcriptase Inhibitors; D003841:Deoxycytidine; C509700:elvitegravir; D000068698:Tenofovir; D000068679:Emtricitabine; D000225:Adenine