November 14, 1997
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Researchers from Johns Hopkins, the Aaron Diamond AIDS Research Center (New York, N.Y.) and the University of California, San Diego, have shown that drug "cocktail" therapy for AIDS does not completely clear the body of HIV. Rather, small amounts of the virus remain "hidden" in immune system cells, unable to cause disease or develop resistance to anti-AIDS drugs.
The findings give hope for long-term survival with HIV infection. But the results also suggest these individuals must continue multiple-drug therapy to prevent reactivation of the infection and active disease. The "cocktail" comprises the relatively new protease inhibitors, plus such long-used drugs as AZT and ddI.
"The bad news is we can't yet get rid of the virus entirely," says Robert F. Siliciano, M.D., associate professor of medicine. "The number of immune system cells that remain infected with HIV declines only very slowly. But the good news is that as long as people infected with HIV keep taking the triple-drug cocktail, they have an excellent chance of surviving the infection for a long time, without developing symptoms of the disease." Siliciano is senior author of an article reporting these results in the Nov. 14 issue of Science.
The study was funded by the National Institutes of Health (Center for AIDS Research) and by the Research Center for AIDS and HIV Infection of the San Diego Veterans Affairs Medical Center.
The new results follow reports by Aaron Diamond researcher David Ho, M.D. that drug cocktail therapy reduced HIV to such low levels it was no longer detectable. Ho suggested that treatment might stop active replication of the virus completely. The present study was undertaken to find and measure HIV "reservoirs" if they existed.
"Ho's idea of measuring the decline in the level of HIV in various reservoirs of the virus was a revolutionary way of looking at the disease," says Siliciano. "Our study identified a specific reservoir that may persist for a long time."
The Hopkins-led researchers studied 22 patients treated with triple-drug therapy for up to 30 months. The patients, who were treated at the Johns Hopkins AIDS Service, received close supervision to ensure they remained on their demanding treatment schedule. This prevented patients from suffering rebounds in their HIV levels and provided the team with a group of individuals with no detectable levels of HIV measurable by standard laboratory methods.
CD4+ lymphocytes are immune system cells targeted by HIV. Most CD4+ lymphocytes infected with HIV produce many copies of the virus before dying. But some of these infected cells survive, become inactive, and enter a resting phase. During the resting phase, these infected cells do not produce new copies of HIV, but remain a reservoir of the virus that triple-drug therapy cannot eliminate, the researchers say.
"We studied patients whose viral loads had been undetectable for prolonged periods of time," says Joel Gallant, M.D., director of the AIDS outpatient clinic. "That kind of success in keeping levels so low was achieved by the combined efforts of our AIDS Service staff and highly motivated patients. That was important in our ability to study HIV in their resting CD4+ cells."
Several Hopkins scientists, led by Joseph B. Margolick, M.D., Ph.D., used a sophisticated cell-sorting technique called flow cytometry to produce very pure populations of resting CD4+ cells from the partially purified cells provided by Siliciano. "We have a special facility for sorting out cells from HIV-infected people, while minimizing hazard to laboratory workers," Margolick says.
"Using the highly purified cells, we found that even after triple-drug therapy reduced HIV to undetectable levels, AIDS virus genetic material remained "hidden" inside "resting" CD4+ lymphocytes," says Diana Finzi, a graduate student working with Siliciano, and lead author of the study. "The team also showed that when the resting cells were stimulated to reproduce, the AIDS virus also replicated."
The multi-institutional study also found that "cocktail" therapy increased the numbers of healthy, uninfected CD4+ cells in all patients--strong evidence that the treatment was successful despite the potentially deadly reservoir of HIV in resting CD4+ cells.
"Fortunately, however, HIV in these resting cells doesn't appear to mutate into drug-resistant forms during triple-drug therapy," Siliciano says. "And because the virus mutates only when it's replicating, this lack of drug resistance suggests the virus is not replicating. So this is a strong argument for not taking these patients off triple-drug therapy."
Other authors of the paper include Martin Markowitz and David Ho (Aaron Diamond AIDS Research Center, New York, N.Y.); Douglas D. Richman (University of California, San Diego); and Monika Hermankova, Theodore Pierson, Lucy M. Carruth, Christopher Buck, Richard Chaisson, Thomas Quinn, Karen Chadwick, and Ronald Brookmeyer (Johns Hopkins).