NEW AIDS FINDINGS ON WHY DRUGS FAIL
By GINA KOLATA
Published: January 12, 1995
New findings about how the AIDS virus behaves in the body help explain why all drugs tried until now have been ineffective, and they cast new light on the reaction of the body's immune system to the invader.
Infection by H.I.V., the human immunodeficiency virus, has been thought of as a gradual process in which the virus acts slowly to undermine the immune system. In fact the virus and the immune system engage in a pitched battle from the very start of infection, according to new findings being published today.
Each day millions of new virus particles are produced and millions are killed. But the immune system's losses are also staggering, with up to one billion infected cells dying and being replaced each day, the new findings show. This battle continues to the end, with the immune system losing just a little ground each day.
The new reports come from the laboratories of two leading AIDS researchers, Dr. David Ho, director of the Aaron Diamond AIDS Research Center in New York, and Dr. George M. Shaw of the University of Alabama in Birmingham. They are being published today in Nature, a prominent scientific journal in London. At a news conference to announce the discoveries, the journals' editors described them as "some of the most significant findings on H.I.V. and AIDS to have appeared in some time."
Dr. Simon Wain-Hobson, who directs the molecular retrovirology laboratory at the Institut Pasteur in Paris, said, "The fact is that these papers are out with a big splash and they are going to concentrate the minds of some people." Dr. Wain-Hobson wrote an editorial accompanying the papers.
Dr. John Coffin, a professor of molecular biology and microbiology at the Tufts University School of Medicine, said the results "really blew me away." Dr. Coffin has written a review explaining the implications of the new findings that will appear soon in Science magazine.
One factor behind the new findings was new drugs that all but stop the AIDS virus in its tracks. By giving these drugs to infected patients and measuring how fast the virus population dives and then recovers, the reseachers were able to calculate the dynamics of infection more precisely.
The AIDS virus is known to make many slightly different or mutated copies of itself, raising the chances that at least one of these mutations will be resistant to any drug. The rapid turnover of virus now known to take place explains why the resistant forms can so quickly predominate in the body after a drug has been administered. The researchers found that the new drugs could destroy 99 percent of the virus in the body, yet resistant strains of virus appeared within days.
The new picture of an AIDS virus infection, scientists say, means that entire research enterprises have gone down the wrong path. It also suggests new strategies for combating the virus: the battle between the immune system and the virus is so close that any drug that weakens the virus and gives the immune system a slight edge might in principle be enough to tip the balance. "We now have some real values to shoot at to try to make an impact on the disease," said Dr. Ho.
When the AIDS virus was first discovered in 1984, researchers thought that the problem of explaining AIDS would be straightforward. H.I.V. attacks a group of white blood cells, known as T4 or CD4 cells, which are an essential component of the body's immune system. It seemed that the disease known as AIDS must be a direct result of this infection.
But in 1986, investigators reported that far too few T4 cells seemed to be infected -- just 1 in 10,000 appeared to harbor the virus. From that emerged what came to be seen as the central mystery of AIDS -- how can so few viruses be killing all those white blood cells? Researchers suggested elaborate explanations as to how the virus might kill T cells indirectly.
Then a few years ago, Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, and Dr. Ashley Haase, a professor of microbiology at the University of Minnesota School of Medicine, discovered a large reservoir of the virus lurking in the lymph nodes, where T cells come to maturity. "Now we know there is a huge mass of infected cells that we hadn't seen before," Dr. Haase said. But that still raised the question of how these infected cells translated into a slow and relentless destruction of the immune system.
Investigators noticed that as an H.I.V. infection progresses, the number of virus particles in circulation gradually increases and the number of T cells gradually dwindles. But no one suspected that this slowly dwindling number was the net result of a constant, raging battle.
Dr. Ho and Dr. Shaw independently realized that they could use powerful new drugs to create a snapshot of the dynamics of an AIDS virus infection in progress. Each team gave the drug to people with AIDS, reducing the H.I.V. population to 1 percent of its former size. Dr. Ho gave ABT-538, an experimental drug that inhibits a crucial viral enzyme called a protease. Dr. Shaw gave the same drug, another protease inhibitor known as L-735,524, and nevirapine, which blocks a different viral enzyme, reverse transcriptase.