Synergistic reduction of HIV-1 infectivity by 5-azacytidine and inhibitors of ribonucleotide reductase.
Although many compounds have been approved for the treatment of human immunodeficiency type-1 (HIV-1) infection, additional anti-HIV-1 drugs (particularly those belonging to new drug classes) are still needed due to issues such as long-term drug-associated toxicities, transmission of drug-resistant variants, and development of multi-class resistance. Lethal mutagenesis represents an antiviral strategy that has not yet been clinically translated for HIV-1 and is based on the use of small molecules to induce excessive levels of deleterious mutations within the viral genome. Here, we show that 5-azacytidine (5-aza-C), a ribonucleoside analog that induces the lethal mutagenesis of HIV-1, and multiple inhibitors of the enzyme ribonucleotide reductase (RNR) interact in a synergistic fashion to more effectively reduce the infectivity of HIV-1. In these drug combinations, RNR inhibitors failed to significantly inhibit the conversion of 5-aza-C to 5-aza-2'-deoxycytidine, suggesting that 5-aza-C acts primarily as a deoxyribonucleoside even in the presence of RNR inhibitors. The mechanism of antiviral synergy was further investigated for the combination of 5-aza-C and one specific RNR inhibitor, resveratrol, as this combination improved the selectivity index of 5-aza-C to the greatest extent. Antiviral synergy was found to be primarily due to the reduced accumulation of reverse transcription products rather than the enhancement of viral mutagenesis. To our knowledge, these observations represent the first demonstration of antiretroviral synergy between a ribonucleoside analog and RNR inhibitors, and encourage the development of additional ribonucleoside analogs and RNR inhibitors with improved antiretroviral activity.
Institute for Molecular Virology, University of Minnesota, 18-242 Moos Tower, 515 Delaware Street SE, Minneapolis, MN 55455, USA; Molecular, Cellular, Developmental Biology & Genetics Graduate Program, University of Minnesota, 321 Church Street SE, Minneapolis, MN 55455, USA.
Jonathan M O
JMO
Rawson
Institute for Molecular Virology, University of Minnesota, 18-242 Moos Tower, 515 Delaware Street SE, Minneapolis, MN 55455, USA; Department of Diagnostic and Biological Sciences, School of Dentistry, University of Minnesota, 515 Delaware Street SE, Minneapolis, MN 55455, USA.
Megan E
ME
Roth
Center for Drug Design, Academic Health Center, University of Minnesota, 516 Delaware Street SE, Minneapolis, MN 55455, USA.
Jiashu
J
Xie
Emory Center for AIDS Research, Emory University, 1518 Clifton Road NE, Suite 8050, Atlanta, GA 30322, USA.
Michele B
MB
Daly
Institute for Molecular Virology, University of Minnesota, 18-242 Moos Tower, 515 Delaware Street SE, Minneapolis, MN 55455, USA; Department of Diagnostic and Biological Sciences, School of Dentistry, University of Minnesota, 515 Delaware Street SE, Minneapolis, MN 55455, USA.
Christine L
CL
Clouser
Department of Computer Science and Engineering, University of Minnesota, 4-192 Keller Hall, 200 Union Street SE, Minneapolis, MN 55455, USA.
Sean R
SR
Landman
Institute for Molecular Virology, University of Minnesota, 18-242 Moos Tower, 515 Delaware Street SE, Minneapolis, MN 55455, USA; Division of Biostatistics, School of Public Health, University of Minnesota, 420 Delaware Street SE, Minneapolis, MN 55455, USA.
Cavan S
CS
Reilly
Center for Drug Design, Academic Health Center, University of Minnesota, 516 Delaware Street SE, Minneapolis, MN 55455, USA.
Laurent
L
Bonnac
Emory Center for AIDS Research, Emory University, 1518 Clifton Road NE, Suite 8050, Atlanta, GA 30322, USA.
Baek
B
Kim
Institute for Molecular Virology, University of Minnesota, 18-242 Moos Tower, 515 Delaware Street SE, Minneapolis, MN 55455, USA; Center for Drug Design, Academic Health Center, University of Minnesota, 516 Delaware Street SE, Minneapolis, MN 55455, USA.
Steven E
SE
Patterson
Institute for Molecular Virology, University of Minnesota, 18-242 Moos Tower, 515 Delaware Street SE, Minneapolis, MN 55455, USA; Department of Diagnostic and Biological Sciences, School of Dentistry, University of Minnesota, 515 Delaware Street SE, Minneapolis, MN 55455, USA; Department of Microbiology and Immunology, Medical School, University of Minnesota, 689 23rd Avenue SE, Minneapolis, MN 55455, USA; Molecular, Cellular, Developmental Biology & Genetics Graduate Program, University of Minnesota, 321 Church Street SE, Minneapolis, MN 55455, USA; Center for Drug Design, Academic Health Center, University of Minnesota, 516 Delaware Street SE, Minneapolis, MN 55455, USA. Electronic address: mansky@umn.edu.
Louis M
LM
Mansky
D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001374:Azacitidine / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
D019380:Anti-HIV Agents; D004791:Enzyme Inhibitors; D012264:Ribonucleotide Reductases; D001374:Azacitidine
5-Azacytidine; Drug synergy; Error catastrophe; HIV-1; Lethal mutagenesis; Resveratrol; Retrovirus; Viral mutagenesis