Los Alamos National Laboratory
John R. Gustafson, 505-665-9197/[email protected]
EMBARGOED until noon MDT, Wednesday, May 7, 1997
NEW DATA, ANALYSIS PROVIDE IMPORTANT INSIGHT INTO BEHAVIOR OF HIV IN BODY
LOS ALAMOS, N.M., May 8, 1997 -- Subjecting new clinical data to a rigorous mathematical analysis, researchers from Los Alamos National Laboratory and the Aaron Diamond AIDS Research Center conclude that combination drug treatment can eliminate the AIDS-causing human immunodeficiency virus from the body's major sites of infection in a few years.
The researchers caution, however, that this does not mean that a cure for AIDS is near at hand. Viral "embers" could lurk in undetected sites in the body or in places where the drugs cannot reach and emerge to rekindle the infection years later.
The study, published in today's issue of the scientific journal Nature, adds important new results to an ongoing collaboration between Los Alamos' Alan Perelson and Paulina Essunger and the Aaron Diamond Center's David Ho and Martin Markowitz, along with other colleagues.
"We've been engaged in a strategy of using potent drugs against HIV to perturb the infectious process, then using the resulting clinical data and mathematical modeling to get insights into the processes going on in the patients," Perelson said.
Earlier studies in the collaboration revealed the lifetime of infected cells actively producing copies of the virus and the incredibly high replication rate of HIV in the body, and thus its ability to mutate and gain resistance to any single drug treatment.
"It's been gratifying that these techniques -- which are mathematical and abstract -- have had an influence on the course of medicine," Perelson said.
The new study tracked eight patients given combinations of drugs designed to fight HIV infection. One drug the patients received (nelfinavir) blocked the action of the viral enzyme protease; if protease doesn't work properly, any new viral particles made as the HIV multiplies are unable to infect new cells. Two other drugs used in the study (zidovudine and lamivudine) inhibited the action of another enzyme, reverse transcriptase, which plays a vital role in HIV's ability to replicate after it enters a cell.
The researchers measured the amount of HIV, also called the "viral load," in each patient's blood plasma at the outset of the study and then at regular intervals as they received the multiple-drug treatment. Confirming earlier results, they found that, in an initial phase, the level of HIV in each patient dropped by between 93 and 99 percent in the first two weeks of treatment as the body eliminated short-lived infected cells and viral particles.
Thereafter the residual viral load decreased at a much slower rate. The researchers believe this slow second phase, which had not been detected in previous studies, reflects the elimination of long-lived cells, such as macrophages, infected before therapy began and possibly viral particles trapped in lymphoid tissues.
The researchers concluded that continuing the combination drug therapy could in two or three years eliminate all HIV from the specific sites of infection they could analyze. New methods will be needed to detect possible lingering infection in other sites in the body to determine the complete effectiveness of such a treatment.
The researchers gained these insights into the behavior of HIV in the body by incorporating the clinical measurements into a detailed mathematical model that Perelson and his colleagues have developed that tracks the interactions between HIV and the various cells in an infected person. For this study they incorporated new terms to account for the sources of infection during the disease's second phase of response to treatment.
The rapid decline in viral load, the researchers said, not only attests to the potency of combination drug treatment but also indicates that a drug-resistant strain of the virus did not emerge during the study period. Researchers have long worried that HIV's ability to mutate rapidly would enable it to evolve and develop resistance to drug treatments.
Although the results of the new study are a positive development, Perelson noted that the people taking part in the study had not previously used any of the drugs given for treatment, and thus the HIV they carried could not have previously had a chance to adapt to the drugs. Others who had received any of the three drugs before could possess HIV more resistant to the drugs and thus respond differently to the combination drug treatment.
Perelson also noted that people in clinical trials generally do much better than people in the general population receiving identical treatment because of the lack of prior exposure to the drugs, the rigor of the treatment protocol and the higher level of overall care people in clinical trials receive.
Perelson, leader of Los Alamos' Theoretical Biology and Biophysics Group, credits the Santa Fe Institute, where he is an external professor and director of the theoretical immunology program, with advancing the team's collaborative discussions. Other authors on the paper are Yunzhen Cao, Mika Vesanen and Arlene Hurley of the Aaron Diamond AIDS Research Center and Kalle Saksela of the University of Tampere in Finland.
Los Alamos National Laboratory is operated by the University of California for the U.S. Department of Energy.
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