Genes That Thwart Apoptosis Pathways May Promote Viral Latency
Research Findings Could Improve Usefulness of Virus as Effective Vector
for Gene Therapy
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."