(Philadelphia, PA) – Researchers at the
University of Pennsylvania School of Medicine have
discovered part of the reason why cold sores, caused by a herpes
virus, come back again and again. The new study, published online
last month in Nature, points to a small RNA molecule, called
a microRNA (miRNA) as the culprit that keeps the latent virus-infected
cell alive. These findings could one day lead to a new way to fight
the virus and offers the first target for intervention in the latent
research team led by Nigel W. Fraser, PhD, Professor
of Microbiology, has found that herpes simplex virus-1 (HSV-1),
the virus that causes cold sores and ocular keratitis, produces
an miRNA molecule. This miRNA is encoded by the Latency-Associated
Transcript gene (LAT) in the viral genome and works through a process
called RNA interference to prevent normal cell death or apoptosis.
Thus, the latent viral infection is maintained for the lifetime
of the individual because the latently infected cell does not die."
“Although miRNAs encoded by cellular genes are known to be
an important mechanism for controlling gene expression, this is
one of the first miRNA found to be encoded by a viral genome,”
says Fraser. “Our study helps show how HSV-1 can maintain
a latent infection for the lifetime of an infected individual.”
The LAT gene was discovered by Fraser and colleagues in 1984, but
a protein product from this gene has never been found. This caused
Fraser and his research team to hypothesize that LAT may work through
an miRNA molecule, which is a small piece of the LAT gene. It interferes
with the translation of two cell proteins that are required for
cell death: TGF-b and SMAD-3. The LAT miRNA binds to specific sequences
of messenger RNA from these two genes and causes them to be degraded.
Thus, the amount of TGF-b and SMAD-3 protein is reduced in the cell
and apoptosis is prevented. Because the latent virus is not producing
any viral proteins the immune system of the infected individual
cannot detect the infected cell.
Latent HSV-1 infections form in neuronal cells of the peripheral
nervous system. When a latent infection is reactivated (by stress
of many kinds), HSV-1 proteins are synthesized and new infectious
virus particles are formed. These virus particles migrate along
the neuronal axons to the epithelial cells of the skin. Viral growth
in the skin, or other mucous membranes where nerves are found, causes
cell damage and an immune reaction that results in a painful sore.
Although the latency-to-reactivation process is not fully understood,
it is known to involve stress, such as physical damage, ultraviolet
light, hormones, or even fever.
Fraser is currently testing whether HSV-2, a relative of HSV-1 that
causes genital herpes, also encodes an miRNA molecule in its LAT
gene. “MiRNA may be a more general mechanism that latent viruses
use to remain alive in the host cell,” suggests Fraser.
Present treatments of HSV-1 rely on acyclovir-based drugs that target
the viral polymerase and inhibit viral DNA replication during the
acute infection. However, they do not target the latent infection,
and thus cold sores return throughout the lifetime of the infected
individual. Finding an miRNA that interacts with the cellular TGF-b
pathway during latency offers the first target against the latent
infection and offers a profoundly different approach to treatment,
The study co-authors are Ananya Gupta, Jarred J. Garner, Praveen
Sethupathy, and Artemis G. Hatzigeorgiou, all from Penn. The study
was funded in part by grants from the National Institutes of Health.
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