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  • thirdmeinvestor thirdmeinvestor May 31, 2006 7:55 PM Flag

    RNAi and cold sore therapy

    Good find. It appears (the Nature article referred to has not been published yet) that HSV uses its own RNAi technology to suppress the cell-suicide genes for its own survival. We can certainly outsmart them to destroy HSV without killing their hiding place, nerve cells. J Lieberman has already done a successful HSV work in mice with siRNA, published in Nature in January this year. This new finding may add another handle to eradicate HSV.

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    • Correction:
      Lieberman's paper I referred to deals with HSV-2 which is sexually transmitted and involved in HIV transmission as well, whereas the new Nature paper deals with HSV-1. However, the latency effect in both types of HSV may involve similar mechanisms; in latency they evade immune detection by not producing proteins, and at the same time using RNA based mechanisms, suppress the cells' last defense, suicide, for their selfish reason, maintenance of infection.

    • Here is first para, Nature:

      Anti-apoptotic function of a microRNA encoded by the HSV-1 latency-associated transcript

      MicroRNAs (miRNAs) are a class of small RNA molecules that regulate the stability or the translational efficiency of target messenger RNAs (mRNAs). The latency-associated transcript (LAT) of herpes simplex virus-1 (HSV-1) is the only viral gene expressed during latent infection in neurons. LAT inhibits apoptosis and maintains latency by promoting the survival of infected neurons. No protein product has been attributed to the LAT gene and the mechanism by which LAT protects cells from apoptosis is not yet known. Here we show that a miRNA encoded by the HSV-1 LAT gene confers resistance to apoptosis. Neuroblastoma cells transfected with a fragment of the LAT gene show reduced susceptibility to cell death. The anti-apoptotic function of LAT has been mapped to a region within the first exon. We have identified and characterized a microRNA (miR-LAT) generated from the exon 1 region of the HSV-1 LAT gene. The LAT miRNA was found to accumulate in cells transiently transfected with the LAT gene fragment or infected with a wild-type strain of HSV-1. A mutant virus in which a 372-nucleotide fragment encompassing the mature miRNA was deleted neither protected the infected cells from apoptosis nor generated an miRNA. miR-LAT exerts its anti-apoptotic effect by downregulation of transforming growth factor (TGF)- 1 and SMAD3 expression, both of which are functionally linked in the TGF- pathway. Our results suggest that the miRNA encoded by the HSV-1 LAT gene regulates the induction of apoptosis in infected cells by modulation of TGF- signalling and thus contributes to the persistence of HSV in a latent form in sensory neurons.

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