Why Herpes Viruses Just Won't Go Away

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Infected for life

How the Herpes Simplex Virus Uses MicroRNA to Hide Out in Cells

(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 infection.

A 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,

concludes Fraser.