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April 23, 2002


Adenovirus Genes That Thwart Apoptosis Pathways May Promote Viral Latency

Research Findings Could Improve Usefulness of Virus as Effective Vector for Gene Therapy

NEW ORLEANS—Scientists from Emory University are studying the specific genetic mechanisms that allow adenoviruses to establish a persistent, latent infection in individuals that lasts for years after the initial illness has cleared. Their findings could prove useful in improving the safety and efficacy of gene therapy using the adenovirus as a vector to deliver genes into the DNA of cells.

Group C adenoviruses infect more than 85% of individuals early in childhood and are the cause of common respiratory illnesses and infant gastroenteritis. Most of these illnesses resolve within two weeks, but studies have shown that the virus establishes a persistent, latent infection, most likely in T lymphocytes.

Adenoviruses can be profoundly pro- or anti-inflammatory, depending on which viral genes are expressed, explains Emory microbiologist Linda Gooding, Ph.D. When adenoviruses are used as vectors, or vehicles to deliver genes into cells in gene therapy experiments, key anti-inflammatory genes are removed.

"Although the adenovirus is being used for gene therapy, there is a big gap in understanding its life cycle," notes Emory microbiologist Linda Gooding, Ph.D. "The problems with using it as a vector are that the virus is quickly cleared from the system, the same vector cannot be used to readminister the virus because of the immune response, and a virus that is profoundly pro-inflammatory can potentially stimulate a strong inflammatory response by the host."

Since the virus remains in the system for a long period of time and does not seem to trigger disease when reactivated, Dr. Gooding and her Emory colleagues wanted to discover which genes in the natural state of the virus within the population of T lymphocytes help it prevent its own rejection and which genes regulate the anti-inflammatory response. "This could help us improve the usefulness of the adenovirus in gene therapy," she said.

Dr. Gooding and graduate student Charlese Garnett studied tissue from tonsils that had been removed from children to look for the presence of adenovirus and to determine genes that might be involved in allowing the adenovirus to establish a persistent infection. They found two mechanisms that might be involved.

In previous research they had discovered several genes within a section of the virus called the E3 transcription unit that interfere with apoptosis signaling — the natural pathway of cell death. In their studies of tonsil tissue, Dr. Gooding, along with graduate student Jeffrey Mahr and microbiologist Jeremy Boss, found that these genes might be activated by T lymphocytes, allowing adenovirus-infected cells to survive during persistent infection.

In additional research, graduate student Adrienne McNees studied a protein complex called the Receptor Internalization and Degradation (RID) complex encoded by the adenovirus genome. The RID complex prevents apoptosis of infected cells by blocking signaling of cell death receptors. The investigators used a retrovirus expressing RID to infect human T lymphocyte cell lines and found that expression of RID in persistently infected lymphocytes could prevent deletion of the adenovirus and facilitate a long-term infection.

"Our research demonstrates several mechanisms that the adenovirus may use to establish a persistent infection," Dr. Gooding says. "With this knowledge, we can now begin to understand how the virus is able to maintain itself for long periods of time in immunocompetent hosts and whether the latent virus contributes to chronic inflammatory disease states."

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