United Press International; Wednesday, September 09, 1998
Lidia Wasowicz, UPI Science Writer

The scientists say in the British journal Nature this is a key discovery because it is this dastardly deed by the human immunodeficiency virus, or HIV, that triggers the chain reaction that leads to the full-blown disease, acquired immune deficiency syndrome, or AIDS.

The scientific sleuths from Texas, California and New York are hopeful the new clues will help solve the puzzle of why some HIV- positive individuals suddenly take a turn for the worse after harboring the virus with no dire consequences for years.

Once they have the whole picture, the investigators say they will be in a far better position to block this sudden, deadly turn of events. "We now know at least one way in which HIV can kill a cell without infecting it. It is likely that this mechanism affects other immune components as well," says Dr. Eric Verdin, an investigator at the Gladstone Institute of Virology and Immunology and professor of medicine at the University of California, San Francisco.

He says the well-known decline in the CD4 immune cells, or helper T- cells, in response to the HIV attack is used as a "surrogate marker" to monitor a patient's progress and response to therapy.

High CD4 counts are a good sign; low counts, an ominous foreshadowing of potentially fatal things to come.

There is another marker in HIV patients -- CD8 T-cells, or killer T- cells, the body's chief weapon against the invading virus. The numbers of these immune cells can remain optimistically high for years -- until suddenly they plummet, no longer able to keep HIV in check.

The latest research gives scientists inside information about this viral strategy. It indicates certain HIV strains that appear in some people during later stages of disease may prompt CD8 cells to commit mass suicide by using one of the immune system's own key players as an accomplice.

"Once patients lose their CD8 T-cells, growth of the virus in CD4 helper cells is probably boosted, and more cells will be killed," says lead study author Dr. Georges Herbein of the Picowar Institute for Medical Research and North Shore University Hospital in New York.

"So you will have an accelerated decline in overall immune function, until the immune system is exhausted."

"Very little is known about how HIV affects cells other than CD4 helper cells," says senior study author Verdin. "Our observations describe a new pathway through which HIV can disturb the function of uninfected cells."

The findings are helping the scientists piece the puzzle pieces together.

Lab and patient studies suggest syncytium inducing, or SI, strains of the virus -- usually associated with a quicker succumbing to AIDS -- increase CD8 cell death to a level so high the body can no longer replace these key warriors.

"SI strains do this by binding to a molecule known as CXCR4, which is present on both CD8 cells and on another crucial immune cell, known as a macrophage," Verdin says. "This CXCR4 binding triggers a suicide response, called apoptosis, in CD8 cells, resulting in their rapid demise."

In the experiments, the increase in CD8 cell death occurred only when macrophages were present. That indicates the virus needed the macrophages to instigate suicide. The accelerated cell death, however, was much less pronounced in the presence of other HIV strains, called non-syncytium inducing, or NSI. These strains are predominant soon after infection.

"It is a surprise that different HIV strains would affect CD8 cells differently, since the virus doesn't infect those cells," says Herbein, an investigator with the AIDS Pathogenesis Research Program at the University of Texas Medical Branch in Galveston. "This is a totally new idea."

The results point to possible ways to block HIV's deadly progression and, at least for some patients, prevent the development of advanced AIDS.

"Right now, everyone's focused on finding ways to block CCR5," a molecule that allows infection by the early HIV strains, Verdin says. "Our research shows it may be just as important to find ways to stop viruses that bind to CXCR4."

The work also suggests patients receiving vaccines that use forms of the HIV envelope protein gp-120 -- known to bind to CXCR4 -- should be closely monitored for effects on CD8 T-cells, Herbein says.

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