|NCI Scientists Discover How T-Cell Leukemia
Viruses Evade Body’s Defense Mechanisms
National Cancer Institute (NCI) scientists have discovered how
human T-cell leukemia virus type 1 (HTLV-1), which infects about
20 million people worldwide, evades being held in check by one
of the body’s natural defense mechanisms. An active infection with
HTLV-1 leads to T-cell leukemia in up to five percent of all cases
worldwide. NCI is part of the National Institutes of Health.
The study, appearing online the week of February 5, 2007 in the Proceedings
of the National Academy of Sciences (PNAS)*,
details how an enzyme, called either APOBEC3G or hA3G, is prevented
from being packaged into virus particles and thus can not perform
its normal function of inhibition of viral replication. When
a virus infects a cell, it replicates its genetic material and
packages it into new virus particles. Preventing the packaging
of hA3G may contribute to the persistence, dissemination, and
the potentially lethal nature of the virus.
The researchers, led by David Derse, Ph.D., in the HIV Drug Resistance
Program at NCI’s Center for Cancer Research in Frederick, Md.,
found that by mutating certain amino acids in the virus capsid,
or core protein, increased levels of hA3G were incorporated into
virus particles. This, in turn, strengthened the ability of hA3G
to inactivate the virus. Non-mutated virus particles maintained
their resistance to hA3G.
“This finding should aid researchers in their basic understanding
of the mechanisms of circumventing viral longevity, and possibly
assist in preventing some types of cancer,” said NCI Director John
E. Niederhuber, M.D.
A number of human and nonhuman viruses that cause cancer or AIDS
are susceptible to hA3G-mediated destruction. However, some viruses
appear to have adapted ways to avoid this intrinsic cellular defense
mechanism. Both HTLV-1 and the AIDS virus, HIV-1, are known to
infect T lymphocyte white blood cells; these cells develop in the
thymus and orchestrate the immune system's response to infected
or malignant cells. But each virus has developed a different method
for thwarting the antiviral effects of hA3G. In HTLV-1, if hA3G
becomes incorporated into viral particles, this can start a process
that will degrade and deactivate the virus itself.
“Our ultimate goal is to try to find a way to block the virus
from being active in the body,” said Derse, “but, before we can
do that, we must have a better understanding of how the virus evades
the natural defenses in the cell that should be fighting off infection.”
An active infection with HTLV-1 usually occurs decades after the
initial infection. As a result, most therapies focus on the cancer
rather than the virus. By enhancing the cell’s intrinsic defense
mechanisms or by interfering with viral resistance to those defenses
early in infection, it may be possible to decrease the incidence
of HTLV-1-associated leukemia. Similar strategies for combating
HIV-1 are also being studied.
One outstanding question in the field continues to be about how
hA3G gets packaged into the virus particle. Derse says “the next
step will be to look at other viruses in relation to HTLV-1 and
examine the mechanisms for evading the body’s natural defenses.”
For more information on Dr. Derse’s research, please go to http://ccr.cancer.gov/Staff/staff.asp?profileid=5504.
For more information about cancer, please visit the NCI Web
site at http://www.cancer.gov,
or call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).
The National Institutes of Health (NIH) — The Nation's
Medical Research Agency — includes 27 Institutes and
Centers and is a component of the U.S. Department of Health and
Human Services. It is the primary federal agency for conducting
and supporting basic, clinical and translational medical research,
and it investigates the causes, treatments, and cures for both
common and rare diseases. For more information about NIH and
its programs, visit www.nih.gov.