Scientists in Texas, California and New York believe they have solved part of the mystery of how the human immunodeficiency virus (HIV) can kill cells it doesn't infect--and thereby prompt the downward spiral that results in AIDS. The results--published in the September 10 issue of the journal Nature--may help researchers and physicians understand what makes HIV-infected people take a sudden turn for the worse after years of harboring the AIDS virus but showing few symptoms. They may also point to new ways of stopping this sudden decline, which ultimately claims the lives of patients with AIDS.
The research was conducted by Eric Verdin, MD, an investigator at the Gladstone Institute of Virology and Immunology and professor of medicine at the University of California San Francisco, and Georges Herbein, MD, PhD, assistant professor of internal medicine at the included researchers at the Picower Institute for Medical Research and North Shore University Hospital in New York.
HIV is well known for causing a decline in immune cells called CD4 or helper T-cells, whose numbers start to drop soon after HIV infection. Doctors use this familiar drop in CD4 cell counts as a so-called surrogate marker to monitor their patients' progress and response to therapy. High levels of helper T-cells are a good sign; low levels are a sign of advancing disease.
But HIV-positive people also lose another set of immune cells, called CD8 T-cells. CD8 cells, also known as killer T-cells, are the body's primary virus-fighting weapon. After HIV infection, their numbers remain generally high, sometimes for years, until a point when they inexplicably begin to die off rapidly. Until then, the killer T cells keep the AIDS virus at bay. As those cells disappear, the virus takes over.
Scientists never knew what triggered this sudden turn of events, but the new research suggests that certain strains of the AIDS virus that appear in some people during later stages of HIV disease may prompt a mass suicide of CD8 cells. What's more, the new study suggests that HIV uses one of the immune system's own key players as an accomplice to promote this self-inflicted death. The result is a sinister snowball effect. "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 Herbein, the study's lead author and an investigator with the AIDS Pathogenesis Research Program in UTMB's division of infectious diseases. "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. Our observations describe a new pathway through which HIV can disturb the function of uninfected cells," says Verdin, senior author of the study and head of the Laboratory of Molecular Virology at the Gladstone Institute.
This research links several previously unconnected observations. For example, scientists knew that CD8 cells of HIV-infected patients have a higher than normal turnover rate, meaning that they die more quickly than normal. The good news is that the lost cells are replaced by the body during the early stages of disease, so that overall CD8 numbers generally remain high. CD8 cells lack a key molecule, known as the CD4 receptor that is present on T helper cells and allows HIV to gain entry to a cell. Since CD8 cells aren't infected by the AIDS virus, scientists weren't sure why they died during HIV disease.
Scientists also knew that patients who carry a certain type of virus known as a syncytium inducing, or SI, strain usually succumb more quickly to AIDS. Since SI strains appear late during the course of HIV infection, scientists never knew whether they were a cause or an effect of those patients' rapid decline. The new research suggests they are a cause. Experiments conducted both in plastic lab dishes and in patients' blood suggest that SI strains increase CD8 cell death to a level so high the body can no longer replace these crucial virus-fighting cells. 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. This CXCR4 binding triggers a suicide response, called apoptosis, in CD8 cells, resulting in their rapid demise.
In the new experiments, the increase in CD8 cell death occurred only when macrophages were present, meaning that HIV needed the macrophages to instigate the CD8 cell suicide. Also, the accelerated CD8 cell death, which occurred when SI strains were present, was much less pronounced in the presence of other strains of the AIDS virus, known as non-syncytium inducing, or NSI, strains. NSI strains are the predominant strains in patients early after HIV infection. "It is a surprise that different HIV strains would affect CD8 cells differently, since the virus doesn't infect those cells," Herbein says. "This is a totally new idea."
These results, say the researchers, raise the possibility that blocking HIV binding to CXCR4 could stop at least some patients from developing advanced AIDS. About half the people with advanced HIV disease harbor a SI strain of the virus.
"Right now, everyone's focused on finding ways to block CCR5," a molecule that allows infection by the NSI, or early, strains of HIV, says Verdin. "Our research shows that it may be just as important to find ways to stop viruses that bind to CXCR4."
The research also suggests that patients receiving vaccines that use forms of the HIV envelope protein, called gp-120, that are known to bind to CXCR4 should be closely monitored for effects on CD8 T-cells, Herbein says.
On a mechanistic level, the new research also suggests one explanation for a paradoxical characteristic of HIV disease: More CD4 helper cells seem to die than are infected with the virus. The new study suggests that macrophages or other immune cells may help HIV kill those cells.
"We now know at least one way in which HIV can kill a cell without infecting it," Verdin says. "It is likely that this mechanism affects other immune components as well."
The J. David Gladstone Institutes are named for a prominent real estate developer who died in 1971. His will created a testamentary trust that reflects his long-standing personal interest in medical education.
The above post is reprinted from materials provided by University Of California, San Francisco. Note: Materials may be edited for content and length.
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