The nucleoside analog 5,6-dihydro-5-aza-2′-deoxycytidine (KP-1212) has been investigated as a first-in-class lethal mutagen of human immunodeficiency virus type-1 (HIV-1). Since a prodrug monotherapy did not reduce viral loads in Phase II clinical trials, we tested if ribonucleotide reductase inhibitors (RNRIs) combined with KP-1212 would improve antiviral activity. KP-1212 potentiated the activity of gemcitabine and resveratrol and simultaneously increased the viral mutant frequency. G-to-C mutations predominated with the KP-1212-resveratrol combination. These observations represent the first demonstration of a mild anti-HIV-1 mutagen potentiating the antiretroviral activity of RNRIs and encourage the clinical translation of enhanced viral mutagenesis in treating HIV-1 infection.
Bibliographical noteFunding Information:
This research was supported by NIH grants R01 GM56615 and R21 AI96937 . J.M.R. was supported by the Institute for Molecular Virology Training Program (NIH grant T32AI83196 ); R.H.H. was supported by the MinnCResT Program (NIH grant T32DE007288 ); L.B.B. was supported by NIH grant F31DA030249 ; J.L.M. was supported by a University of Minnesota Basic Sciences PhD Graduate Programs Council Fellowship; M.J.D. was supported by NIH grant T32DA007097 . Combustion analysis of KP-1212 and gemcitabine was performed by Atlantic Microlab, Inc. (Norcross, GA). The authors would like to thank Laurent Bonnac for performing 1 H NMR of KP-1212 and Cavan Reilly for suggestions regarding statistical tests and procedures.
- Error catastrophe
- Lethal mutagenesis