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Author Notes:

Address correspondence to Elena I. Frolova, efrolova@uab.edu, or Ilya Frolov, ivfrolov@uab.edu.

We thank Maryna Akhrymuk for technical assistance.

Subjects:

Research Funding:

This study was supported by Defense Threat Reduction Agency contract HDTRA1-15-C-0075 to G.R.P. and Public Health Service grants AI118867 to E.I.F. and AI095449 to I.F.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Virology
  • alphaviruses
  • antivirals
  • N-hydroxycytidine
  • RNA-dependent RNA polymerase
  • Venezuelan equine encephalitis virus
  • drug-resistant mutant
  • lethal mutagenesis
  • VENEZUELAN EQUINE ENCEPHALITIS
  • VIRUS-RNA REPLICATION
  • LETHAL MUTAGENESIS
  • ERROR CATASTROPHE
  • RIBAVIRIN RESISTANCE
  • ANTIVIRAL ACTIVITY
  • MOSQUITO CELLS
  • POLYMERASE
  • POLIOVIRUS
  • FIDELITY

beta-D-N-4-Hydroxycytidine Is a Potent Anti-alphavirus Compound That Induces a High Level of Mutations in the Viral Genome

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Journal Title:

Journal of Virology

Volume:

Volume 92, Number 3

Publisher:

Type of Work:

Article | Final Publisher PDF

Abstract:

Venezuelan equine encephalitis virus (VEEV) is a representative member of the New World alphaviruses. It is transmitted by mosquito vectors and causes highly debilitating disease in humans, equids, and other vertebrate hosts. Despite a continuous public health threat, very few compounds with anti-VEEV activity in cell culture and in mouse models have been identified to date, and rapid development of virus resistance to some of them has been recorded. In this study, we investigated the possibility of using a modified nucleoside analog, β-D-N4-hydroxycytidine (NHC), as an anti-VEEV agent and defined the mechanism of its anti-VEEV activity. The results demonstrate that NHC is a very potent antiviral agent. It affects both the release of genome RNA-containing VEE virions and their infectivity. Both of these antiviral activities are determined by the NHC-induced accumulation of mutations in virus-specific RNAs. The antiviral effect is most prominent when NHC is applied early in the infectious process, during the amplification of negative- and positive-strand RNAs in infected cells. Most importantly, only a low-level resistance of VEEV to NHC can be developed, and it requires acquisition and cooperative function of more than one mutation in nsP4. These adaptive mutations are closely located in the same segment of nsP4. Our data suggest that NHC is more potent than ribavirin as an anti- VEEV agent and likely can be used to treat other alphavirus infections.

Copyright information:

© 2018 American Society for Microbiology.

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