5,6-Dihydro-5-aza-2'-deoxycytidine potentiates the anti-HIV-1 activity of ribonucleotide reductase inhibitors

Abstract

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.

Keywords: 2′,2′-difluoro-2′-deoxycytidine; 2′,2′-difluoro-2′-deoxyuridine; 5,6-Dihydro-5-aza-2′-deoxycytidine; 5-AZC; 5-aza-5,6,-dihydro-2′-deoxycytidine; 5-azacytidine; DMSO; Error catastrophe; KP-1212; Lethal mutagenesis; MOI; NRTI; RNRI; Resveratrol; SD; dFdC; dFdU; dimethylsulfoxide; multiplicity of infection; nucleoside reverse transcriptase inhibitor; ribonucleotide reductase inhibitor; standard deviation.