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2/22/97
KEY MOLECULE FOUND CRITICAL TO SURVIVING HIV
STANFORD -- Researchers at Stanford have found that HIV patients with ample levels of a small, hardworking molecule normally found throughout the body are likely to outlive patients whose stores are low.
The more of these molecules patients carry in their CD4 T cells (the primary cells targeted by the HIV virus), the longer the patients are likely to survive, report Leonore and Leonard Herzenberg, genetics professors at the Stanford University School of Medicine.
The molecule, called glutathione, plays a role in many of the body's normal activities, ranging from cell division to mopping up oxidants and other toxic molecules.
"It's been known since 1989 that people with HIV have CD4 cells deficient in glutathione. Now we know that glutathione levels matter to patients' survival," said Leonard Herzenberg, who will present the new finding Saturday, Feb. 22, at the annual meeting of the American Association of Immunologists, in San Francisco.
The Herzenbergs' finding could help doctors treat HIV disease more effectively, perhaps by preventing further loss of glutathione or by boosting its levels in patients who need more of it, he said.
The finding also raises the possibility that drugs such as the common painkiller acetaminophen (sold under the brand name Tylenol and others) are hazardous to people with HIV or with other conditions that suppress immune function, added Leonore Herzenberg.
"What we show for the first time in this work is that people with HIV who have lower glutathione levels have a much lower probability of surviving over the course of three years than do people with normal glutathione levels," Leonard Herzenberg said.
The study also demonstrates that glutathione levels can be used with CD4 counts for a more reliable indicator of the progression of HIV disease, according to the researchers.
Clinicians today commonly track the progression of HIV disease by measuring the total number of CD4 cells in a blood sample; patients with low counts are considered at risk of earlier death due to HIV. "But total CD4 counts don't reliably predict how long an individual patient is likely to live or how rapidly the person's disease will progress. Some patients with low CD4 counts unexpectedly survive for a very long time," Leonore Herzenberg said.
The Herzenbergs, a well-known husband-and-wife research team at Stanford, worked with study coordinator Greg Dubs; genetics research fellows Dr. Stephen De Rosa, Mario Roederer, Michael Anderson and Stephen Ela; and clinical assistant professor of medicine Dr. Stanley Deresinski. A full report of their findings will appear in the March 4 issue of the journal Proceedings of the National Academy of Sciences, the Herzenbergs said.
A total of 204 patients took part in the study. When the patients joined the study, all of them were HIV positive but had no outward signs of illness. Over the next three years, the researchers found that patients who maintained normal glutathione levels -- even if their CD4 counts were low -- tended to outlive those with low glutathione levels.
The study included 99 patients with CD4 counts below 200 cells per microliter of blood -- the threshold clinicians view as an imminent threat to survival. Most patients who had such low levels of CD4 cells and also had low levels of glutathione died within three years.
"In contrast, of the 28 people who started the study with low CD4 counts but maintained normal glutathione levels, 23 survived. In other words, about 80 percent of these people survived, even though their CD4 cell counts indicated their survival was unlikely," Leonard Herzenberg said.
The researchers stress the importance of maintaining adequate levels of glutathione for HIV patients.
One potential way to do this, they suggest, is to give HIV patients a drug called N-acetylcysteine (NAC), which is normally used to treat acetaminophen overdose. Their study showed that daily NAC tablets were able to boost the glutathione in patients' blood to a healthy level.
The study also raises concerns about acetaminophen use by people with HIV. "Our findings lead us to ask two questions: Is it safe for people with HIV to take acetaminophen and other drugs that deplete their stores of glutathione? And should all HIV patients take a drug like NAC that will help to maintain their glutathione levels?" Leonard Herzenberg said.
The Herzenbergs, together with John James, publisher of the San Francisco-based newsletter AIDS Treatment News, are asking the Food and Drug Administration to consider requiring drug companies to label glutathione-depleting drugs such as acetaminophen with a warning stating the potential hazard to people with HIV.
With regard to taking NAC, Leonard Herzenberg said: "We know low glutathione indicates a bad prognosis for survival for HIV patients. We know that NAC will raise glutathione levels in patients. Therefore, it's logical to suggest that NAC will help HIV patients live longer.
"But we don't know this for sure," he said. "That's why the next step should be a clinical trial to see whether NAC will increase HIV patients' long-term survival."
The newly reported research was funded in part by the National Cancer Institute.
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