SV40-encoded microRNAs regulate viral gene expression and reduce susceptibility to cytotoxic T cells (original) (raw)

Nature volume 435, pages 682–686 (2005)Cite this article

Abstract

MicroRNAs (miRNAs) are small (∼ 22-nucleotide) RNAs that in lower organisms serve important regulatory roles in development and gene expression, typically by forming imperfect duplexes with target messenger RNAs1. miRNAs have also been described in mammalian cells and in infections with Epstein–Barr virus (EBV), but the function of most of them is unknown. Although one EBV miRNA probably altered the processing of a viral mRNA2, the regulatory significance of this event is uncertain, because other transcripts exist that can supply the targeted function3. Here we report the identification of miRNAs encoded by simian virus 40 (SV40) and define their functional significance for viral infection. SVmiRNAs accumulate at late times in infection, are perfectly complementary to early viral mRNAs, and target those mRNAs for cleavage. This reduces the expression of viral T antigens but does not reduce the yield of infectious virus relative to that generated by a mutant lacking SVmiRNAs. However, wild-type SV40-infected cells are less sensitive than the mutant to lysis by cytotoxic T cells, and trigger less cytokine production by such cells. Thus, viral evolution has taken advantage of the miRNA pathway to generate effectors that enhance the probability of successful infection.

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Acknowledgements

We thank M. McManus, J. Ziegelbauer and J. Bechtel for discussions; P. Otohal and M. Epler for their assistance in CTL assays; and B. Garcea for the gift of VP1 antibody. This work was supported by the Howard Hughes Medical Institute. S.T. and J.M.P. are supported by NIH grants.Author Contributions C.S.S. conceived the project and carried out all experiments in Figs 1–4c. D.G. directed and supervised the experimental work and interpretation. A.T.G. developed and applied the computational algorithm for miRNA detection, and assisted in the design of the SM mutant. J.M.P. assisted with project planning, provided viral strains and participated in data review. S.T. designed and carried out the CTL lysis experiments. All authors participated in the drafting of the manuscript.

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Authors and Affiliations

  1. Howard Hughes Medical Institute and Departments of Microbiology and Medicine, G. W. Hooper Foundation, University of California, San Francisco, California, 94143-0552, USA
    Christopher S. Sullivan, Adam T. Grundhoff & Don Ganem
  2. Department of Microbiology and Immunology, The Pennsylvania State College of Medicine, Hershey, Pennsylvania, 17033, USA
    Satvir Tevethia
  3. Department of Biological Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania, 15260, USA
    James M. Pipas

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  1. Christopher S. Sullivan
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  2. Adam T. Grundhoff
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  3. Satvir Tevethia
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  4. James M. Pipas
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  5. Don Ganem
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Correspondence toDon Ganem.

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Sullivan, C., Grundhoff, A., Tevethia, S. et al. SV40-encoded microRNAs regulate viral gene expression and reduce susceptibility to cytotoxic T cells.Nature 435, 682–686 (2005). https://doi.org/10.1038/nature03576

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Editorial Summary

Viral microRNAs

MicroRNAs are a large class of noncoding small RNAs, about 22 nucleotides in length, thought to target other genes and regulate their expression. Their regulatory role has been demonstrated in lower organisms: microRNAs are present in mammals including humans, though their role in higher organisms is not clear. Now they have been found to have a function in virus biology. SV40 virus encodes several microRNAs involved in the late stages of infection of monkey cells. These microRNAs maintain viral replicative efficiency by reducing excess antigen production. It has been suggested that inhibitory RNA systems in mammals are there as a defence against viruses, suggesting that what is normally an antiviral defence pathway is being subverted by the virus for its own purposes.