Herpes Simplex Virus

Humans are infected by two closely related but distinct herpes simplex viruses, Herpes Simplex Virus Type I (HSV-1), also known as oral herpes, and HSV-2, also known as genital herpes. HSV-1 initially infects the mucosa around the mouth and gives rise to an inflammatory lesion which is rapidly cleared by the immune system. However, during the primary infection HSV-1 establishes a latent infection in the neuronal cells of the trigeminal ganglion. In these non-dividing cells, the HSV-1 DNA genome exists as an episomal DNA circle that is almost transcriptionally inert, with the exception of a single major RNA transcript, the latency associated transcript LAT. LAT was known to regulate HSV-1 latency but the underlying mechanism had remained obscure. A major step forward in understanding HSV-1 latency was achieved in 2008 with the demonstration by the Cullen laboratory that LAT is processed to give rise to six HSV-1 miRNAs and that latent HSV-1 also expresses a seventh miRNA from a previously unknown pri-miRNA. Moreover, the Cullen laboratory demonstrated that these viral miRNAs target mRNAs encoding the two key HSV-1 regulatory proteins ICP0 and ICP4 for downregulation, thus stabilizing HSV-1 latency.

Similar to HSV-1, HSV-2 initially infects the genital mucosa and then establishes latency in neurons of the sacral ganglia. HSV-2 also expresses miRNAs that are similar to those encoded by HSV-1 and these also regulate HSV-2 latency by an apparently similar mechanism. The main questions we are dealing with at present are as follows:

  1. What other mRNAs are targeted by the HSV-1 and HSV-2 miRNAs and how does this affect viral replication?
  2. Do cellular miRNAs regulate HSV-1 and/or HSV-2 gene regulation and does this affect viral latency?
  3. In collaboration with Professor David Bloom (Univ. of Florida), we are generating HSV-1 mutants lacking one or more viral miRNAs to unequivocally demonstrate that these miRNAs do play a key role in regulating viral latency in vivo.
  4. We are initiating experiments designed to address whether inhibition of viral miRNA function can reactivate latent viral infections with a view to generating proof-of-principle data demonstrating that HSV-1 and HSV-2 miRNAs are good targets for intervention in infected patients.