Concomitant lethal mutagenesis of human immunodeficiency virus type 1

Michael J. Dapp, Colleen M. Holtz, Louis M. Mansky

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)158-170
Number of pages13
JournalJournal of Molecular Biology
Volume419
Issue number3-4
DOIs
StatePublished - Jun 8 2012

Bibliographical note

Funding Information:
We thank Christine Clouser, Holly Sadler, Steve Patterson, and Reuben Harris for helpful comments and suggestions. We also thank Igor Rogozin for help with the use of CLUSTERM for hotspot prediction analysis. This research was supported by National Institutes of Health grant R01 GM56615 . M.J.D. was supported by National Institutes of Health grant T32DA007097 , and C.M.H., by T32DE007288 .

Keywords

  • deamination
  • evolution
  • lentivirus
  • retrovirus
  • transversion

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