The antiretrovirus drug 3'-azido-3'-deoxythymidine increases the retrovirus mutation rate.

Important note: Information in this article was accurate in 1997. The state of the art may have changed since the publication date.

The antiretrovirus drug 3'-azido-3'-deoxythymidine increases the retrovirus mutation rate.

J Virol. 1997 Jun;71(6):4254-63. Unique Identifier : AIDSLINE MED/97296228
Julias JG; Kim T; Arnold G; Pathak VK; Department of Biochemistry, Mary Babb Randolph Cancer Center,; West Virginia University, Morgantown 26506, USA.

Abstract: It was previously observed that the nucleoside analog 5-azacytidine increased the spleen necrosis virus (SNV) mutation rate 13-fold in one cycle of retrovirus replication (V. K. Pathak and H. M. Temin, J. Virol. 66:3093-3100, 1992). Based on this observation, we hypothesized that nucleoside analogs used as antiviral drugs may also increase retrovirus mutation rates. We sought to determine if 3'-azido-3'-deoxythymidine (AZT), the primary treatment for human immunodeficiency virus type 1 (HIV-1) infection, increases the retrovirus mutation rate. Two assays were used to determine the effects of AZT on retrovirus mutation rates. The strategy of the first assay involved measuring the in vivo rate of inactivation of the lacZ gene in one replication cycle of SNV- and murine leukemia virus-based retroviral vectors. We observed 7- and 10-fold increases in the SNV mutant frequency following treatment of target cells with 0.1 and 0.5 microM AZT, respectively. The murine leukemia virus mutant frequency increased two- and threefold following treatment of target cells with 0.5 and 1.0 microM AZT, respectively. The second assay used an SNV-based shuttle vector containing the lacZ alpha gene. Proviruses were recovered as plasmids in Escherichia coli, and the rate of inactivation of lacZ alpha was measured. The results indicated that treatment of target cells increased the overall mutation rate two- to threefold. DNA sequence analysis of mutant proviruses indicated that AZT increased both the deletion and substitution rates. These results suggest that AZT treatment of HIV-1 infection may increase the degree of viral variation and alter virus evolution or pathogenesis.

Keywords: Antiviral Agents/*PHARMACOLOGY Base Sequence Dose-Response Relationship, Drug DNA, Viral/BIOSYNTHESIS Leukemia Viruses, Murine/GENETICS Molecular Sequence Data Mutagenesis/*DRUG EFFECTS Proviruses/GENETICS Reticuloendotheliosis Virus, Avian/GENETICS Retroviridae/*GENETICS RNA-Directed DNA Polymerase/METABOLISM Sequence Deletion Support, U.S. Gov't, P.H.S. Virus Replication Zidovudine/*PHARMACOLOGY JOURNAL ARTICLE
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