Researchers Uncover How Some Aids Drugs May Cause Cardiovascular Problems
Findings should help drug designers develop new medications with fewer side effects
EMBARGOED UNTIL FRIDAY, NOV. 30, 2001 AT 2 P.M., EST
NEW YORK, Nov. 30—Researchers have uncovered important clues about how certain anti-AIDS drugs, called protease inhibitors, may lead to the severe cardiovascular problems suffered by many patients taking the medications. The findings, to be published in the December issue of Nature Medicine, could help drug developers create a next-generation AIDS medication that would not have the same side effects. For the past six years, people infected with HIV have been living longer as a result of taking a three-component cocktail of AIDS drugs that includes an HIV protease inhibitor. All the drugs act to keep the virus at low levels in the body and prevent the destruction of the immune system that is characteristic of AIDS. But as people have been taking these drugs, particularly protease inhibitors, for longer periods of time, many have developed dangerous problems with fat metabolism, including a disfiguring redistribution of fat in the body called lipodystrophy and high levels of cholesterol and fat (triglyceride) in the blood stream. Although patients taking these anti-HIV drugs may not progress to AIDS, they could have an increased risk of mortality due to cardiovascular events. In the study, a team of scientists at Columbia University College of Physicians & Surgeons in collaboration with an Australian researcher analyzed how protease inhibitors damage the ability of liver cells grown in culture to assemble lipoprotein particles. Lipoprotein particles, also known as VLDLs, LDLs and HDLs, are large complexes of molecules that transport cholesterol, triglycerides and other fats through the blood. Liver cells also manufacture apolipoproteins, which sit on the surface of the lipoprotein to direct the particles where to deliver their cargo inside the body. Fat is used for energy in the body and cholesterol is a key component of cell membranes, but too much fat and cholesterol in the blood can clog arteries. The researchers found that protease inhibitors cause the accumulation inside the liver cell of a certain apolipoprotein, called apolipoprotein B, because the drugs act to block their breakdown. The drugs also simultaneously prevent apolipoprotein B from being secreted by the liver cell. Apolipoprotein B is a critical component of the VLDL lipoprotein particle. VLDLs are a precursor to LDLs, the so-called bad cholesterol, high levels of which increase the risk of heart disease. After the liver cell secretes VLDLs into the bloodstream and the body uses the fat inside, the particles become LDLs. In normal liver cells, half of the apolipoprotein B molecules are degraded before the formation of VLDL. But the cells treated with protease inhibitors were laden with apolipoprotein B. The researchers also found that the stockpiling of apoliprotein B inside the cell caused by the protease inhibitors can be relieved by giving the cell a fatty acid, a component of fat. The fatty acid allows the liver cell to release supra-normal amounts of the apolipoprotein B-VLDL particles. The findings, the scientists say, suggest that the accumulation of apolipoprotein B in liver cells in the presence of protease inhibitors represents a population of newborn lipoprotein particles ready for release into the blood stream. Based on the data, the investigators hypothesize that high levels of VLDLs and LDLs found in the blood stream of individuals taking protease inhibitors could be due to excess particles that get released after the consumption of fatty meals, which contain fatty acids. Although the problem protease inhibitors inflict on apolipoprotein B levels may help explain some of the cardiovascular side effects of these medications, other drugs in the cocktail also affect the mitochondrion, the part of the cell machinery responsible for generating energy. Mitochondria use constituents of fat as fuel for energy. The researchers say the liver cell assay systems used in their study might help drug developers design new protease inhibitors that would not lead to the accumulation of apolipoprotein B inside the cell. The cell systems also can be used to distinguish the extent of the apolipoprotein effect with the protease inhibitors currently in use.
· The research was performed by Dr. Jun-Shan Liang, a postdoctoral fellow in the laboratory of Dr. Henry Ginsberg, director of the Irving Center for Clinical Research and Irving Professor of Medicine at P&S; and by Mr. Oliver Distler, a student working in the laboratory of Dr. Stephen Sturley, assistant professor of human nutrition (in pediatrics and the Institute of Human Nutrition) at P&S. Mr. Distler is on loan from Dr. David Cooper of the University of New South Wales in Sydney, Australia. Dr. Richard Deckelbaum, professor of pediatrics and director of the Institute of Human Nutrition at P&S, also contributed to the study.
· The study was supported by Glaxo-Wellcome, Roche Products, Merck & Co., the National Institutes of Health and the Columbia-Rockefeller Center for AIDS Research. The Australian Commonwealth of Health and Aged Care also supported two members of the team.