TUPE017 - Poster Exhibition
Delayed emergence of HIV-1 variants resistant to 4'-ethnyl-2-fluoro-2'-deoxyadenosine (EFdA): comparative sequential passage study with tenofovir, emtricitabine and festinavir
K. Maeda1, D. Desai1, H. Nakata1,2, H. Mitsuya1,2
1National Institutes of Health, National Cancer Institute, Bethesda, United States, 2Kumamoto University, Kumamoto, Japan
Background: EFdA, a novel RTI, exerts potent activity against
various HIV-1 strains including multi-drug-resistant variants with IC50 values of 0.05-0.4 nM. HIV-1
develops moderate level resistance against EFdA; however, more detailed
development feature of EFdA resistance remains to be determined.
Methods: Comparative sequential passage study was conducted
with EFdA, 3TC, TDF, and
2´,3´-didehydro-3´-deoxy-4´-ethynylthymidine (Ed4T/festinavir), using a mixture of 11 highly multi-drug resistant clinical HIV-1 strains as a
starting virus population. The
mixed population was first propagated in MT4 cells and subjected to selection
Results: HIV11MIX was
sensitive to EFdA, TDF, and Ed4T with IC50 values of 0.006, 0.051, 0.46 µM, respectively, but was highly resistant
to 3TC (IC50 value >10 µM).
It took only 10 passages
for the concentration of Ed4T, under which HIV11MIX robustly replicated, to
reach 10 µM; while it took 18 passages for TDF to reach
10 µM. It took 10 passages for
EFdA to reach 500 nM and the concentration barely reached 3 µM by passage
24. The IC50 values of
TDF against HIV11MIX exposed to
EFdA and TDF for 10 passages (HIV11MIXEFdA-R and HIV11MIXTDF-R)
were 8 and >10 µM, while those of EFdA were 0.2 and 0.1 µM,
respectively. AZT, 3TC, Ed4T, and emtricitabine
were virtually inert (IC50 values >10 µM). A clinical isolate, CLHIVC, was found predominant (~70%) in HIV11MIX
before selection and contained M41L/E44D/D67N/T69D/M184V/L210W/T215Y/K219N. HIV11MIXEFdA-R and HIV11MIXTDF-R
K219Q. The additions and changes, D67del/T69G/K70R/L74I/T215F/K219Q, were thought to be
derived from another clinical isolate, CLHIVB.
Conclusions: The data strongly suggest that
mixed HIV-1 population develops resistance against TDF and Ed4T more rapidly
than against EFdA through homologous recombination, that EFdA resistance
development significantly delays, and that EFdA remains substantially active
against TDF- and EFdA-selected variants.
Thus, EFdA has a unique resistance profile and represents a promising
new generation RTI.
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