MicroRNAs expressed by Herpes simplex virus 1 during latent infection regulate viral mRNAs

Umbach, J. L., M. F. Kramer, I. Jurak, H. W. Karnowski, D. M. Coen, and B. R. Cullen.

2008. Nature 454:780-3.

Speaker: Hsung-Yun Hu (胡瑄耘)                                  Time: 15:00~16:00, Nov. 12, 2008

Commentator: Shun-hua Chen, Ph.D. (陳舜華老師)              Place: Room 601

Abstract:

Herpes simplex virus (HSV) is a member of Hepesviridae, which is a double stranded DNA virus that can cause latent infections. The latent infection and reactivation of HSV-1 primarily take place in sensory neurons, especially in trigeminal ganglia. During latency, latency-associated transcripts (LAT) are abundantly expressed (1). However, the mechanism of LAT to regulate latent infection is still poorly understood. MicroRNAs (miRNAs) are short, ~22 nucleotide, non-coding RNAs that are derived form short hairpin precursors. MiRNAs can target specific mRNAs and regulate many mechanisms, such as cell proliferation, differentiation, and apoptosis. The first miRNA was discovered in Caenorhabditis elegans and the first viral miRNA was found in EBV in 2004 (3). The authors showed that the LAT transcripts are the primary miRNA precursors of four distinct miRNAs (2). The authors found a fifth miRNA which is derived from an unknown primary miRNA precursor that lies antisense to the LAT promoter. They show that miR-H2-3p from LAT can bind to ICP0 mRNA, which is responsible for a transcriptional activator, expressed as an immediate-early gene, which promotes viral replication and facilitates reactivation from latency. The fifth miR-H6 can bind to ICP4 mRNA, which is responsible for a transcription factor required for expression of most HSV-1 gene during productive infection. Both miR-H2-3p and miR-H6 can reduce the protein expression of ICP0 and ICP4, but can not suppress the levels of mRNA indicating a post-transcriptional regulation of viral gene expression. In conclusion, HSV-1 express at least two primary miRNA precursors in latent infection. MiRNA may be the key regulator to inhibit viral transcription related factor expression and to enter as well as maintain latency.

References:

1.         Bloom, D. C. 2004. HSV LAT and neuronal survival. Int Rev Immunol 23:187-98.

2.         Cui, C., A. Griffiths, G. Li, L. M. Silva, M. F. Kramer, T. Gaasterland, X. J. Wang, and D. M. Coen. 2006. Prediction and identification of herpes simplex virus 1-encoded microRNAs. J Virol 80:5499-508.

3.         Pfeffer, S., M. Zavolan, F. A. Grasser, M. Chien, J. J. Russo, J. Ju, B. John, A. J. Enright, D. Marks, C. Sander, and T. Tuschl. 2004. Identification of virus-encoded microRNAs. Science 304:734-6.