Infected For Life

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Infected For Life

15 Jun 2006

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.

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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.

This release and related images can also be seen at:

http://www.uphs.upenn.edu/news

PENN Medicine is a $2.9 billion enterprise dedicated to the related

missions of medical education, biomedical research, and high-quality

patient care. PENN Medicine consists of the University of Pennsylvania

School of Medicine (founded in 1765 as the nation's first medical

school) and the University of Pennsylvania Health System.

Penn's School of Medicine is ranked number 2 in the nation for receipt

of NIH research funds; and ranked number4 in the nation in U.S. News and

World Report's most recent ranking of top research-oriented medical

schools. Supporting 1,400 fulltime faculty and 700 students, the School

of Medicine is recognized worldwide for its superior education and

training of the next generation of physician-scientists and leaders of

academic medicine.

The University of Pennsylvania Health System includes three hospitals

[Hospital of the University of Pennsylvania, which is consistently

ranked one of the nation's few " Honor Roll " hospitals by U.S. News &

World Report; Pennsylvania Hospital, the nation's first hospital; and

Penn Presbyterian Medical Center]; a faculty practice plan; a

primary-care provider network; two multispecialty satellite facilities;

and home care and hospice.

Contact: Kreeger

University of Pennsylvania School of Medicine

Article URL: http://www.medicalnewstoday.com/medicalnews.php?newsid=45096