Scientists discover how T-cell leukemia viruses evade defense mechanisms

Feb 6 2007

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."