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| HSV-1: LAT-eral thinking
Herpes simplex virus-1 (HSV-1) uses an RNA interference strategy to downregulate TGF-β signaling and prevent host cell apoptosis. Herpes simplex virus-1 is most commonly associated with oral herpes. It infects mucosal surfaces and establishes latency in the nervous system. Latency-associated transcript (LAT) is the only viral gene expressed during latent infection in sensory neurons. Previous studies have shown that LAT inhibits neuronal apoptosis, but its mechanism of action is unknown. In Nature, Gupta et al. report that the HSV-1 LAT gene encodes a micro RNA (miRNA) that prevents apoptosis in infected cells by modulating TGF-ß signaling.
Gupta et al. confirm that LAT expression reduces the susceptibility of SY5Y and HeLa cells to stress-induced cell death. Furthermore, they found that short interfering RNA (siRNA)-mediated silencing of the RNase III enzyme Dicer reduced the anti-apoptotic function of LAT, suggesting that LAT encodes an miRNA. In agreement with these results, exon 1 of LAT contains a hairpin loop characteristic of precursor miRNAs, and cells transfected with a LAT deletion construct — which lacks a 372 nucleotide fragment containing the predicted mature miRNA — were not protected from apoptosis. MiRNAs are small ‘noncoding' or 'non-messenger' RNAs which regulate the translation of target messenger RNAs. Computational analysis using miRanda identified transforming growth factor ß (TGF-ß) and SMAD3 as putative targets of LAT miRNA. Indeed, both proteins are involved in the regulation of cell death through the TGF-ß signaling pathway and contain conserved sequences with partial homology to LAT miRNA. Importantly, the levels of endogenous TGF-ß and SMAD3, as well as the transcription of TGF-ß responsive genes, were remarkably reduced in cells expressing LAT or infected with a wild-type strain of HSV-1. Downregulation of either TGF- In summary, this study shows that HSV-1 uses an RNA interference mechanism to establish latency. LAT miRNA prevents host cell apoptosis and contributes to the persistence of HSV-1 infection by downregulating TGF-ß signaling. The ability to do this without synthesizing a viral protein may be a common mechanism of latent viruses to evade immune detection. Monica Hoyos-Flight, Online Editor
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or SMAD3 by siRNA also conferred resistance to apoptosis, indicating that the anti-apoptotic function of LAT miRNA is achieved through inhibition of TGF-ß signaling. 