Research unveils mystery of HIV’s death pathway

Virus strains affect CD8 T-cells differently

Why do some HIV-infected people suddenly develop full-blown AIDS after harboring the virus for years without showing many symptoms?

In a study reported in the Sept. 10 issue of Nature, a group of microbiologists suggests that strains of the AIDS virus appear to use the immune system’s own virus-fighting capabilities to trigger a mass suicide of immune cells.1

The immune cells, called CD8 T-cells, are often referred to as "killer" T-cells and are the body’s primary disease-fighting weapon. The number of CD8 cells remains very stable until one or two years before the onset of AIDS. A massive death of CD8 cells will exhaust the patient’s immune system and increase the risk of pneumonia and other infections that lead to death.

In laboratory experiments conducted thus far, researchers have identified the means by which the virus affects the CD8 cells, and at least one HIV strain that seems to trigger the dramatic cell suicide.

The findings could help drug makers identify new ways to prevent the virus from attacking CD8 cells, says George Herbein, MD, PhD, assistant professor of internal medicine at the University of Texas Medical Branch at Galveston. "Even more importantly, patients receiving current vaccines that involve the gp120 envelope protein should be closely monitored for effects on CD8 T-cells," adds Herbein. (See related story, p. 133.)

The missing link

Researchers have long known that HIV infects one type of immune cell — the CD4 or "helper" T-cell — by locking onto a molecule on the cell wall and invading the cell. Measurements of CD4 cell levels are used as a marker of a patient’s pro gress. High levels of T-cells are a good sign; low levels indicate advancing disease. Levels of the virus-fighting CD8 cells, thought to have better protection from HIV, also have been used as an indicator of how well the body is fending off the AIDS virus.

However, the cause of the quick and massive death of CD8 cells has been a mystery. It is not understood how HIV can affect CD8 cells, because CD8 cells lack a key molecule known as the CD4 adaptor, which is present on helper T-cells and allows HIV to gain entry to a cell. CD8 cells are not infected by the AIDS virus, so researchers weren’t sure why CD8 cells died during HIV disease.

Researchers say the "death pathway" is a complex and dynamic process involving communication between CD8 T-cells and macrophages, another population of immune cells. They also found that different HIV strains affect CD8 cells differently.

A strain of virus known as syncytium-inducing (SI) strain, which appears late in the course of HIV infection, binds to a molecule known as CXCR4, which is present on both CD8 cells and on macrophages. This CXCR4 binding triggers apoptosis — death — in CD8 cells.

When SI strains are present with other strains of the virus, called non-syncytium-inducing (NSI) strains, CD8 cell death is more moderate. In the early stages of infection, patients generally have NSI strains. SI strains don’t appear until later in the disease.

Why should the death signal be sent in the first place? Researchers say the virus may reduce the immune system’s "social control" over its own cells. The regulation of programmed cell death, it seems, is coupled with the processes of cell differentiation, proliferation, and migration.

"Because CD8 T-cells are professional killers, they may do serious harm if they end up in the wrong place," says Jean Claude Ameisen,PhD, of Hopital Bichat/Universite Paris, in an essay accompanying the study.2 Also, because CD8 cells are thought to limit the spread of infection, the failure of the CD8 function could contribute to the development of AIDS, adds Herbein.

References

1. Herbein G, Mahlknecht U, Batiwalla F. Apoptosis of CD8+ T cells is mediated by macrophage through interaction of HIV gp120 with chemokine receptor CXCR4. Nature 1998; 395:189-194.

2. Ameisen J. Setting death in motion. Nature 1998; 395: 117-118.