Viruses and microRNAs: RISCy interactions with serious consequences.

Analyses of small RNA expression profiles have revealed that several DNA viruses-including particularly, herpesviruses-express high levels of multiple viral microRNAs (miRNAs) in infected cells. Here, I review our current understanding of how viral miRNAs influence viral replication and pathogenesis and discuss how viruses reshape the pattern of cellular miRNA expression. Indeed, viruses are now known to both activate and repress the expression of specific cellular miRNAs, and disrupting this process can perturb the ability of viruses to replicate normally. In addition, it is now clear that virally encoded miRNAs play a key role in inhibiting antiviral innate immune responses and can also promote cell transformation in culture. While our understanding of how viruses interact with miRNAs remains somewhat rudimentary, it is nevertheless already clear that these interactions can play a critical role in mediating viral pathogenesis and therefore may represent novel and highly specific targets for therapeutic intervention.

[1]  Adam Grundhoff,et al.  Virus-encoded microRNAs. , 2011, Virology.

[2]  J. Steitz,et al.  Comprehensive Analysis of Rhesus Lymphocryptovirus MicroRNA Expression , 2010, Journal of Virology.

[3]  Jay Nelson,et al.  Identification and Characterization of Human Cytomegalovirus-Encoded MicroRNAs , 2005, Journal of Virology.

[4]  D. Ganem,et al.  Tandem array–based expression screens identify host mRNA targets of virus-encoded microRNAs , 2009, Nature Genetics.

[5]  Michael Niepmann,et al.  microRNA-122 stimulates translation of hepatitis C virus RNA , 2008, The EMBO journal.

[6]  Louis Flamand,et al.  Identification of functional microRNAs released through asymmetrical processing of HIV-1 TAR element† , 2008, Nucleic acids research.

[7]  Ben Berkhout,et al.  HIV-1 can escape from RNA interference by evolving an alternative structure in its RNA genome , 2005, Nucleic acids research.

[8]  R. Shiekhattar,et al.  The Microprocessor complex mediates the genesis of microRNAs , 2004, Nature.

[9]  Doron Betel,et al.  Widespread regulatory activity of vertebrate microRNA* species. , 2011, RNA.

[10]  S. Kauppinen,et al.  Therapeutic Silencing of MicroRNA-122 in Primates with Chronic Hepatitis C Virus Infection , 2010, Science.

[11]  M. Lacey,et al.  MicroRNA-155 Is an Epstein-Barr Virus-Induced Gene That Modulates Epstein-Barr Virus-Regulated Gene Expression Pathways , 2008, Journal of Virology.

[12]  J. Burnside,et al.  Sequence Conservation and Differential Expression of Marek's Disease Virus MicroRNAs , 2008, Journal of Virology.

[13]  Jing Xia,et al.  Identification of Novel MicroRNA-Like Molecules Generated from Herpesvirus and Host tRNA Transcripts , 2010, Journal of Virology.

[14]  B. Cullen,et al.  Viruses, microRNAs, and host interactions. , 2010, Annual review of microbiology.

[15]  B. Ramratnam,et al.  Human Immunodeficiency Virus Type 1 Escape from RNA Interference , 2003, Journal of Virology.

[16]  Alexandra Schäfer,et al.  Epstein–Barr Virus MicroRNAs Are Evolutionarily Conserved and Differentially Expressed , 2006, PLoS pathogens.

[17]  Venugopal Nair,et al.  Critical Role of the Virus-Encoded MicroRNA-155 Ortholog in the Induction of Marek's Disease Lymphomas , 2011, PLoS pathogens.

[18]  Asaf Levy,et al.  Discovery of microRNAs and other small RNAs in solid tumors , 2010, Nucleic acids research.

[19]  Guanming Wu,et al.  A Viral microRNA Down-Regulates Multiple Cell Cycle Genes through mRNA 5′UTRs , 2010, PLoS pathogens.

[20]  A. Saïb,et al.  A Cellular MicroRNA Mediates Antiviral Defense in Human Cells , 2005, Science.

[21]  J. Cohen,et al.  An acutely and latently expressed herpes simplex virus 2 viral microRNA inhibits expression of ICP34.5, a viral neurovirulence factor , 2008, Proceedings of the National Academy of Sciences.

[22]  B. Cullen Transcription and processing of human microRNA precursors. , 2004, Molecular cell.

[23]  V. Kim,et al.  The Drosha-DGCR8 complex in primary microRNA processing. , 2004, Genes & development.

[24]  P. Krause,et al.  Novel Less-Abundant Viral MicroRNAs Encoded by Herpes Simplex Virus 2 Latency-Associated Transcript and Their Roles in Regulating ICP34.5 and ICP0 mRNAs , 2008, Journal of Virology.

[25]  B. O'Hara,et al.  Evolutionarily Conserved Function of a Viral MicroRNA , 2008, Journal of Virology.

[26]  Viraj R Sanghvi,et al.  A Re-Examination of Global Suppression of RNA Interference by HIV-1 , 2011, PloS one.

[27]  D. Ganem,et al.  Murine Polyomavirus encodes a microRNA that cleaves early RNA transcripts but is not essential for experimental infection. , 2009, Virology.

[28]  Andrea J. O'Hara,et al.  EBV microRNAs in primary lymphomas and targeting of CXCL-11 by ebv-mir-BHRF1-3. , 2008, Cancer research.

[29]  C. Croce Causes and consequences of microRNA dysregulation in cancer , 2009, Nature Reviews Genetics.

[30]  P. Sarnow,et al.  Modulation of Hepatitis C Virus RNA Abundance by a Liver-Specific MicroRNA , 2005, Science.

[31]  B. Cullen Is RNA interference involved in intrinsic antiviral immunity in mammals? , 2006, Nature Immunology.

[32]  S. Pfeffer,et al.  Post-transcriptional regulation of miR-27 in murine cytomegalovirus infection. , 2010, RNA.

[33]  Zhen Lin,et al.  Epstein-Barr Virus Latent Membrane Protein 1 Induces Cellular MicroRNA miR-146a, a Modulator of Lymphocyte Signaling Pathways , 2007, Journal of Virology.

[34]  M. Watson,et al.  MicroRNA Profile of Marek's Disease Virus-Transformed T-Cell Line MSB-1: Predominance of Virus-Encoded MicroRNAs , 2008, Journal of Virology.

[35]  J. Ziegelbauer,et al.  Regulation of Tumor Necrosis Factor-Like Weak Inducer of Apoptosis Receptor Protein (TWEAKR) Expression by Kaposi's Sarcoma-Associated Herpesvirus MicroRNA Prevents TWEAK-Induced Apoptosis and Inflammatory Cytokine Expression , 2010, Journal of Virology.

[36]  Alberto Riva,et al.  Kaposi's Sarcoma-Associated Herpesvirus Encodes an Ortholog of miR-155 , 2007, Journal of Virology.

[37]  C. S. Sullivan,et al.  Expanding the role of Drosha to the regulation of viral gene expression , 2011, Proceedings of the National Academy of Sciences.

[38]  Jirí Vanícek,et al.  Suppression of immediate-early viral gene expression by herpesvirus-coded microRNAs: Implications for latency , 2008, Proceedings of the National Academy of Sciences.

[39]  Blossom Damania,et al.  Kaposi's sarcoma-associated herpesvirus expresses an array of viral microRNAs in latently infected cells. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[40]  Eugene Berezikov,et al.  Mammalian mirtron genes. , 2007, Molecular cell.

[41]  Hanah Margalit,et al.  Host Immune System Gene Targeting by a Viral miRNA , 2007, Science.

[42]  K. Roemer,et al.  Epstein–Barr virus-encoded microRNA miR-BART2 down-regulates the viral DNA polymerase BALF5 , 2007, Nucleic acids research.

[43]  Xiaowei Wang,et al.  A Functional MicroRNA-155 Ortholog Encoded by the Oncogenic Marek's Disease Virus , 2008, Journal of Virology.

[44]  C. Sander,et al.  Identification of microRNAs of the herpesvirus family , 2005, Nature Methods.

[45]  H. Margalit,et al.  Cytomegalovirus microRNAs Facilitate Persistent Virus Infection in Salivary Glands , 2010, PLoS pathogens.

[46]  B. Cullen,et al.  A Viral microRNA Cluster Strongly Potentiates the Transforming Properties of a Human Herpesvirus , 2011, PLoS pathogens.

[47]  D. Kwong,et al.  An Epstein-Barr virus–encoded microRNA targets PUMA to promote host cell survival , 2008, The Journal of experimental medicine.

[48]  B. Cullen,et al.  Exportin-5 mediates the nuclear export of pre-microRNAs and short hairpin RNAs. , 2003, Genes & development.

[49]  B. Cullen,et al.  Structural requirements for pre-microRNA binding and nuclear export by Exportin 5. , 2004, Nucleic acids research.

[50]  Scot E Dowd,et al.  Small RNA profiling reveals antisense transcription throughout the KSHV genome and novel small RNAs. , 2010, RNA.

[51]  Anton J. Enright,et al.  Identification of Virus-Encoded MicroRNAs , 2004, Science.

[52]  C. Thurner,et al.  Functional microRNA generated from a cytoplasmic RNA virus , 2010, Nucleic acids research.

[53]  M. Samols,et al.  Cloning and Identification of a MicroRNA Cluster within the Latency-Associated Region of Kaposi's Sarcoma-Associated Herpesvirus , 2005, Journal of Virology.

[54]  E. Izaurralde,et al.  Gene silencing by microRNAs: contributions of translational repression and mRNA decay , 2011, Nature Reviews Genetics.

[55]  T. Du,et al.  Asymmetry in the Assembly of the RNAi Enzyme Complex , 2003, Cell.

[56]  S. Hammond,et al.  An RNA-directed nuclease mediates post-transcriptional gene silencing in Drosophila cells , 2000, Nature.

[57]  Byoung-Tak Zhang,et al.  Molecular Basis for the Recognition of Primary microRNAs by the Drosha-DGCR8 Complex , 2006, Cell.

[58]  S. Russell,et al.  Engineering microRNA responsiveness to decrease virus pathogenicity , 2008, Nature Medicine.

[59]  J. Steitz,et al.  Down-Regulation of a Host MicroRNA by a Herpesvirus saimiri Noncoding RNA , 2010, Science.

[60]  Frances Gotch,et al.  miR-132 regulates antiviral innate immunity through suppression of the p300 transcriptional co-activator , 2010, Nature Cell Biology.

[61]  A. García-Sastre,et al.  Engineered RNA viral synthesis of microRNAs , 2010, Proceedings of the National Academy of Sciences.

[62]  S. Jayasena,et al.  Functional siRNAs and miRNAs Exhibit Strand Bias , 2003, Cell.

[63]  Bryan R. Cullen,et al.  A viral microRNA functions as an orthologue of cellular miR-155 , 2007, Nature.

[64]  L. Xing,et al.  Epstein-Barr Virus BHRF1 Micro- and Stable RNAs during Latency III and after Induction of Replication , 2007, Journal of Virology.

[65]  L. Laimins,et al.  Human Papillomaviruses Modulate Expression of MicroRNA 203 upon Epithelial Differentiation to Control Levels of p63 Proteins , 2010, Journal of Virology.

[66]  T. Margolis,et al.  Herpes Simplex Virus 2 MicroRNA miR-H6 Is a Novel Latency-Associated Transcript-Associated MicroRNA, but Reduction of Its Expression Does Not Influence the Establishment of Viral Latency or the Recurrence Phenotype , 2011, Journal of Virology.

[67]  J. Mellor,et al.  Numerous Conserved and Divergent MicroRNAs Expressed by Herpes Simplex Viruses 1 and 2 , 2010, Journal of Virology.

[68]  B. Cullen,et al.  A Human Herpesvirus MicroRNA Inhibits p21 Expression and Attenuates p21-Mediated Cell Cycle Arrest , 2010, Journal of Virology.

[69]  G. Hannon,et al.  Processing of primary microRNAs by the Microprocessor complex , 2004, Nature.

[70]  J. Haas,et al.  Systematic analysis of viral and cellular microRNA targets in cells latently infected with human gamma-herpesviruses by RISC immunoprecipitation assay. , 2010, Cell host & microbe.

[71]  Katherine Cosmopoulos,et al.  Comprehensive Profiling of Epstein-Barr Virus MicroRNAs in Nasopharyngeal Carcinoma , 2008, Journal of Virology.

[72]  Bryan R. Cullen,et al.  Virally Induced Cellular MicroRNA miR-155 Plays a Key Role in B-Cell Immortalization by Epstein-Barr Virus , 2010, Journal of Virology.

[73]  Kwok Wai Lo,et al.  Modulation of LMP1 protein expression by EBV-encoded microRNAs , 2007, Proceedings of the National Academy of Sciences.

[74]  D. Spector,et al.  A Human Cytomegalovirus-Encoded microRNA Regulates Expression of Multiple Viral Genes Involved in Replication , 2007, PLoS pathogens.

[75]  James M. Pipas,et al.  SV40-encoded microRNAs regulate viral gene expression and reduce susceptibility to cytotoxic T cells , 2005, Nature.

[76]  B. Cullen,et al.  Adenovirus VA1 Noncoding RNA Can Inhibit Small Interfering RNA and MicroRNA Biogenesis , 2004, Journal of Virology.

[77]  A. Rossi,et al.  Epstein–Barr virus latent membrane protein 1 trans-activates miR-155 transcription through the NF-κB pathway , 2008, Nucleic acids research.

[78]  Noam Stern-Ginossar,et al.  Diverse herpesvirus microRNAs target the stress-induced immune ligand MICB to escape recognition by natural killer cells. , 2009, Cell host & microbe.

[79]  Martin Reczko,et al.  Discrete Clusters of Virus-Encoded MicroRNAs Are Associated with Complementary Strands of the Genome and the 7.2-Kilobase Stable Intron in Murine Cytomegalovirus , 2007, Journal of Virology.

[80]  B. Cullen,et al.  Analysis of Human Alphaherpesvirus MicroRNA Expression in Latently Infected Human Trigeminal Ganglia , 2009, Journal of Virology.

[81]  U. Kutay,et al.  Nuclear Export of MicroRNA Precursors , 2004, Science.

[82]  Robert E. White,et al.  An ATM/Chk2-mediated DNA damage responsive signaling pathway suppresses Epstein-Barr virus transformation of primary human B cells , 2010, Cell host & microbe.

[83]  B. Cullen,et al.  A mammalian herpesvirus uses noncanonical expression and processing mechanisms to generate viral MicroRNAs. , 2010, Molecular cell.

[84]  S. Sengupta,et al.  The microRNAs of Epstein-Barr Virus are expressed at dramatically differing levels among cell lines. , 2009, Virology.

[85]  Scott B. Dewell,et al.  Transcriptome-wide Identification of RNA-Binding Protein and MicroRNA Target Sites by PAR-CLIP , 2010, Cell.

[86]  B. Cullen,et al.  MicroRNAs expressed by herpes simplex virus 1 during latent infection regulate viral mRNAs , 2008, Nature.

[87]  N. Raab-Traub,et al.  The Epstein-Barr Virus BART microRNAs target the pro-apoptotic protein Bim. , 2011, Virology.

[88]  Ben Berkhout,et al.  Suppression of RNA Interference by Adenovirus Virus-Associated RNA , 2005, Journal of Virology.

[89]  S. Le,et al.  Evidence that HIV-1 encodes an siRNA and a suppressor of RNA silencing. , 2005, Immunity.

[90]  B. Cullen,et al.  Transcriptional Origin of Kaposi's Sarcoma-Associated Herpesvirus MicroRNAs , 2006, Journal of Virology.

[91]  S. Pfeffer,et al.  Mouse Cytomegalovirus MicroRNAs Dominate the Cellular Small RNA Profile during Lytic Infection and Show Features of Posttranscriptional Regulation , 2007, Journal of Virology.

[92]  Margaret S. Ebert,et al.  MicroRNA sponges: competitive inhibitors of small RNAs in mammalian cells , 2007, Nature Methods.

[93]  Paul Kellam,et al.  KSHV-encoded miRNAs target MAF to induce endothelial cell reprogramming. , 2010, Genes & development.

[94]  Pascal Barbry,et al.  Suppression of MicroRNA-Silencing Pathway by HIV-1 During Virus Replication , 2007, Science.

[95]  N. Rajewsky,et al.  A human snoRNA with microRNA-like functions. , 2008, Molecular cell.

[96]  R. Shiekhattar,et al.  TRBP recruits the Dicer complex to Ago2 for microRNA processing and gene silencing , 2005, Nature.

[97]  J. Steitz,et al.  The Herpesvirus saimiri Small Nuclear RNAs Recruit AU-Rich Element-Binding Proteins but Do Not Alter Host AU-Rich Element-Containing mRNA Levels in Virally Transformed T Cells , 2004, Molecular and Cellular Biology.

[98]  Hong Cao,et al.  Cellular microRNA and P bodies modulate host-HIV-1 interactions. , 2009, Molecular cell.

[99]  Simon S. McDade,et al.  MicroRNA 203 Expression in Keratinocytes Is Dependent on Regulation of p53 Levels by E6 , 2010, Journal of Virology.

[100]  Bryan R. Cullen,et al.  Analysis of the Interaction of Primate Retroviruses with the Human RNA Interference Machinery , 2007, Journal of Virology.

[101]  B. Cullen,et al.  Analysis of rhesus rhadinovirus microRNAs expressed in virus-induced tumors from infected rhesus macaques. , 2010, Virology.

[102]  Robert Blelloch,et al.  Mouse ES cells express endogenous shRNAs, siRNAs, and other Microprocessor-independent, Dicer-dependent small RNAs. , 2008, Genes & development.

[103]  B. Cullen,et al.  Recognition and cleavage of primary microRNA precursors by the nuclear processing enzyme Drosha , 2005, The EMBO journal.

[104]  Yutaka Tsutsumi,et al.  HIV-1 nef suppression by virally encoded microRNA , 2004, Retrovirology.

[105]  L. Laimins,et al.  p63 Is Necessary for the Activation of Human Papillomavirus Late Viral Functions upon Epithelial Differentiation , 2011, Journal of Virology.

[106]  Alberto Riva,et al.  Identification of Cellular Genes Targeted by KSHV-Encoded MicroRNAs , 2007, PLoS pathogens.

[107]  Bryan R. Cullen,et al.  In-Depth Analysis of Kaposi's Sarcoma-Associated Herpesvirus MicroRNA Expression Provides Insights into the Mammalian MicroRNA-Processing Machinery , 2009, Journal of Virology.

[108]  Ker-Chau Li,et al.  Enterovirus-induced miR-141 contributes to shutoff of host protein translation by targeting the translation initiation factor eIF4E. , 2011, Cell host & microbe.

[109]  W. Hammerschmidt,et al.  Micro RNAs of Epstein-Barr Virus Promote Cell Cycle Progression and Prevent Apoptosis of Primary Human B Cells , 2010, PLoS pathogens.

[110]  D. Bartel MicroRNAs: Target Recognition and Regulatory Functions , 2009, Cell.

[111]  N. Van Rooijen,et al.  Use of Tissue-Specific MicroRNA to Control Pathology of Wild-Type Adenovirus without Attenuation of Its Ability to Kill Cancer Cells , 2009, PLoS pathogens.

[112]  Catherine L Jopling,et al.  Position-dependent function for a tandem microRNA miR-122-binding site located in the hepatitis C virus RNA genome. , 2008, Cell host & microbe.

[113]  M. Vignuzzi,et al.  Harnessing endogenous miRNAs to control virus tissue tropism as a strategy for developing attenuated virus vaccines. , 2008, Cell host & microbe.

[114]  D. Bartel,et al.  Intronic microRNA precursors that bypass Drosha processing , 2007, Nature.