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SV40-encoded microRNAs regulate viral gene expression and reduce susceptibility to cytotoxic T cells

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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Figure 1: SV40 encoded miRNAs.
Figure 2: Fine mapping of SV40 pre-miRNA and miRNAs.
Figure 3: A role for SV40miRNAs in cleavage of early mRNAs.
Figure 4: Phenotype of the SM mutant.

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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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Correspondence to Don Ganem.

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Supplementary information

Supplementary Figure S1

Computational prediction of SV40 microRNAs (PDF 106 kb)

Supplementary Figure S2

Sequence of SV40miRNA mutant. (PDF 64 kb)

Supplementary Figure S3

CTL lysis and gamma IFN relase assays with CT clone K-11 (I) of WT versus SM. (PDF 92 kb)

Supplementary Figure S4

VirMir plots and structural predictions of SVpre-miRNA homologues present in other Polyomaviruses. (PDF 368 kb)

Supplementary Figure Legends

Legends to accompany Supplementary Figures S1-S4. (DOC 22 kb)

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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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