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20 December 2000
New Approach To AIDS Treatment
by George Atkinson

Researchers at the University of Colorado Health Sciences Center have shown in laboratory studies that a molecule found in the human body can halt the growth of the AIDS virus. In a paper accepted for publication in the Federation of the American Societies of Experimental Biology (FASEB) Journal (January 1, 2001), the researchers describe various ways in which alpha-1 antitrypsin (AAT), a naturally-occurring protein in blood, prevents the AIDS virus from reproducing and from being spread to healthy cells. The AAT used in these investigations was purified from the blood of healthy volunteers who donated blood for research to the American Red Cross.

This novel path in AIDS research was led by Leland Shapiro, MD, assistant professor of medicine at CU-Health Sciences Center and principal investigator of the study. Several observations led the research team to search for a potent natural AIDS inhibitor in blood.

"In the laboratory, we confirmed the surprising observation that the AIDS virus did not grow in blood," Dr. Shapiro said. "This suggested that there was at least one substance in the blood that blocked the virus. We believe we have identified one of the substances as AAT, the most abundant inhibitor of serine proteases (natural enzymes that degrade proteins) in the blood."

The laboratory results were dramatic. Dr. Shapiro observed that although the AIDS virus did not proliferate when added to blood obtained from healthy volunteers, the virus replicated readily when added to blood from patients who had reduced AAT due to a genetic defect.

In other studies, the team found that in special cells designed to detect infection with the AIDS virus, AAT blocked the ability of the virus to infect previously healthy, uninfected cells. The research team next studied cells chronically infected with the AIDS virus. These cells can be induced by a variety of stimuli to produce high levels of AIDS virus. When these cells were stimulated in the presence of AAT, however, viral production was reduced by 90 percent to 100 percent compared to cells without AAT present.

This effect was observed regardless of the stimulus used to increase virus production in the cells. AAT also was able to stop replication of AIDS virus in natural, freshly infected blood mononuclear cells, a type of blood cell involved in fighting infections and healing wounds.

Dr. Shapiro and the research team propose that although AAT exists normally in the body, the AIDS virus appears to reproduce in areas where the amounts of AAT are low, such as in the lymph glands. By injecting infected patients with AAT it might be possible to increase AAT at the sites of viral replication. This might bolster the defense against the virus by preventing the production of AIDS virus from infected cells and blocking the spread of virus to healthy cells.

The research group also described experiments using a synthetic inhibitor of host serine proteases developed by Cortech to function as an AAT "mimic." This synthetic "mimic" possessed nearly identical effects as naturally-occurring AAT in inhibiting the AIDS virus. This suggests to the researchers that an oral agent (pill) eventually might be designed to treat AIDS.

"These findings are preliminary but promising," Dr. Shapiro said. "Inhibitors of serine proteases should be considered as candidates for treating the AIDS virus. If clinical results are as promising as what we have seen in the laboratory, methods of increasing AAT or use of an AAT "mimic" might be an effective form of AIDS therapy." Dr. Shapiro adds that the results of this research suggest that this approach to treatment may work regardless of viral mutations.

Clinical trials will be proposed to the AIDS Clinical Trials Group, which is based at the CU-Health Sciences Center. Additional laboratory studies and clinical studies in human subjects are required to determine the effectiveness of serine protease inhibitors like AAT or the AAT "mimic" in battling AIDS.

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