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Journal of Virology, November 2009, p. 11950-11958, Vol. 83, No. 22
0022-538X/09/$08.00+0     doi:10.1128/JVI.01406-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

5-Azacytidine Can Induce Lethal Mutagenesis in Human Immunodeficiency Virus Type 1{triangledown} ,{dagger}

Michael J. Dapp,1,5 Christine L. Clouser,1 Steven Patterson,1,2 and Louis M. Mansky1,2,3,4*

Institute for Molecular Virology,1 Center for Drug Design, Academic Health Center,2 Department of Diagnostic and Biological Sciences, School of Dentistry,3 Departments of Microbiology,4 Pharmacology, Medical School, University of Minnesota, Minneapolis, Minnesota 554555

Received 9 July 2009/ Accepted 21 August 2009

Ribonucleosides inhibit human immunodeficiency virus type 1 (HIV-1) replication by mechanisms that have not been fully elucidated. Here, we report the antiviral mechanism for the ribonucleoside analog 5-azacytidine (5-AZC). We hypothesized that the anti-HIV-1 activity of 5-AZC was due to an increase in the HIV-1 mutation rate following its incorporation into viral RNA during transcription. However, we demonstrate that 5-AZC's primary antiviral activity can be attributed to its effect on the early phase of HIV-1 replication. Furthermore, the antiviral activity was associated with an increase in the frequency of viral mutants, suggesting that 5-AZC's primary target is reverse transcription. Sequencing analysis showed an enrichment in G-to-C transversion mutations and further supports the idea that reverse transcription is an antiviral target of 5-AZC. These results indicate that 5-AZC is incorporated into viral DNA following reduction to 5-aza-2'-deoxycytidine. Incorporation into the viral DNA leads to an increase in mutant frequency that is consistent with lethal mutagenesis during reverse transcription as the primary antiviral mechanism of 5-AZC. Antiviral activity and increased mutation frequency were also associated with the late phase of HIV-1 replication; however, 5-AZC's effect on the late phase was less robust. These results reveal that the primary antiviral mechanism of 5-AZC can be attributed to its ability to increase the HIV-1 mutation frequency through viral-DNA incorporation during reverse transcription. Our observations indicate that 5-AZC can affect two steps in HIV-1 replication (i.e., transcription and reverse transcription) but that its primary antiviral activity is due to incorporation during reverse transcription.

* Corresponding author: Institute for Molecular Virology, University of Minnesota, 18-242 Moos Tower, 515 Delaware St. SE, Minneapolis, MN 55455. Phone (612) 626-5525. Fax: (612) 626-5515. E-mail: mansky{at}umn.edu

{triangledown} Published ahead of print on 2 September 2009.

{dagger} Supplemental material for this article may be found at http://jvi.asm.org/.

Journal of Virology, November 2009, p. 11950-11958, Vol. 83, No. 22
0022-538X/09/$08.00+0     doi:10.1128/JVI.01406-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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