Concomitant Lethal Mutagenesis of Human Immunodeficiency Virus Type 1

JOURNAL OF MOLECULAR BIOLOGY

卷:419

Article

Dapp, Michael J.^1,2,3,4  Holtz, Colleen M.^1,2  Mansky, Louis M.^1,2,3,4,5 

[1] Univ Minnesota, Inst Mol Virol, Acad Hlth Ctr, Minneapolis, MN 55455 USA

[2] Univ Minnesota, Dept Diagnost & Biol Sci, MinnCResT Program, Sch Dent, Minneapolis, MN 55455 USA

[3] Univ Minnesota, Ctr Drug Design, Acad Hlth Ctr, Minneapolis, MN 55455 USA

[4] Univ Minnesota, Pharmacol Grad Program, Sch Med, Minneapolis, MN 55455 USA

[5] Univ Minnesota, Dept Microbiol, Sch Med, Minneapolis, MN 55455 USA

关键词: lentivirus;    retrovirus;    evolution;    deamination;    transversion;   

DOI  :  10.1016/j.jmb.2012.03.003

来源: Elsevier

【 摘 要 】

RNA virus population dynamics are complex, and sophisticated approaches are needed in many cases for therapeutic intervention. One such approach, termed lethal mutagenesis, is directed at targeting the virus population structure for extinction or error catastrophe. Previous studies have demonstrated the concept of this approach with human immunodeficiency virus type 1 (HIV-1) by use of chemical mutagens [i.e., 5-azacytidine (5-AZC)] as well as by host factors with mutagenic properties (i.e., APOBEC3G). In this study, these two unrelated mutagenic agents were used concomitantly to investigate the interplay of these distinct mutagenic mechanisms. Specifically, an HIV-1 was produced from APOBEC3G (A3G)-expressing cells and used to infect permissive target cells treated with 5-AZC. Reduced viral infectivity and increased viral mutagenesis were observed with both the viral mutagen (i.e., G-to-C mutations) and the host restriction factor (i.e., G-to-A mutations); however, when combined, they had complex interactions. Intriguingly, nucleotide sequence analysis revealed that concomitant HIV-1 exposure to both 5-AZC and A3G resulted in an increase in G-to-A viral mutagenesis at the expense of G-to-C mutagenesis. A3G catalytic activity was required for the diminution in G-to-C mutagenesis. Taken together, our findings provide the first demonstration for potentiation of the mutagenic effect of a cytosine analog by A3G expression, resulting in concomitant HIV-1 lethal mutagenesis. (C) 2012 Elsevier Ltd. All rights reserved.

【 授权许可】

Free