Project Inform Analysis: Results of a "Cure" Study
The August 12, 2005 issue of The Lancet reported on the results of a study which attempted to reduce the reservoir of cells that are latently infected with HIV. In theory, a treatment that could achieve this perfectly might result in an outright cure of HIV disease since scientists believe it is the continued presence of this reservoir that makes HIV infection a permanent condition. This study was one of series of steps researchers have taken attempting to deal with the problem of the reservoir of HIV-infected cells. Unfortunately, the magazine splashed the word CURE all over its cover, raising inappropriate expectations about what the study was able to accomplish.
These latently infected cells are normally not affected by anti-HIV drugs because they are inactive and not producing virus. Thus, the anti-HIV drugs have no effect on them. Most anti-HIV drugs only work with cells that are active, HIV-infected and producing new copies of virus. Additionally, when HIV-infected cells are inactive, they are also not recognized by the immune system as a problem, again because they are not producing virus or doing anything the immune system recognizes as "wrong." Thus, they "fly under the radar" of the immune system and remain a constant, unchecked threat. Any time the latently infected cell "wakes up" or is activated, it begins producing new copies of HIV. Thus, the body never rids itself of HIV. Some is always left in reserve.
This particular approach to reducing the reservoir described in The Lancet article was proposed and discussed in Project Inform's Immune Restoration Think Tank several years ago. It was proposed at that time by Dr. David Margolis, whose lab managed the study mentioned in The Lancet article. The general model of attempting a "cure" in this fashion was in fact proposed by immunologist Max Cooper of Alabama at the very first meeting of the Think Tank back in 1991, when the meeting was hosted by the National Academy of Science's Institute of Medicine. Project Inform has described this potential approach to a cure in a number of articles over the years. For those wanting more background, consider the following (available through Project Inform's Infoline and website):
PI Perspective #26, 1998 -- Interleukin-2: A Path Toward Functional Eradication?
PI Perspective #24, 1998 -- HIV Eradication: Dead or Alive, or Even Necessary?
PI Perspective #19, 1996 -- Eradication of HIV: Hope or Hype?
PI Perspective #17, 1995 -- Four New Concepts for Combating HIV Infection
The basic idea of flushing the reservoir begins with providing maximum suppression of viral replication by whatever means available. This is to make sure that no new HIV is created in the body or allowed to infect cells while the effort to clear the reservoir takes place. In this case, the small study reported in The Lancet included four people whose HIV levels were already "undetectable" while on anti-HIV therapy. Their treatment was then intensified with the addition of a potent new drug, T20 (enfuvirtide, Fuzeon). Up to this point, Margolis' approach was similar to earlier efforts to rid the body of HIV. But his approach differed in the next step. Earlier efforts by other researchers added another type of drug that was intended to "activate" the latently infected cells in the reservoirs. The hope was that this would make the cells visible to the immune system as they began to produce HIV, leading to their eventual death, while the standard anti-HIV drugs blocked any new virus from infecting other cells. These past approaches failed, either because the effort to activate the cells proved too toxic, or because it failed to activate all the latently infected cells.
Margolis' team tried a different approach at this step. They added a well known and quite safe anti-convulsive drug, valproic acid, to the patients' daily regimens. Recent research had shown that the drug seemed to interfere with the process that allowed some HIV-infected cells to become dormant in the first place. Those cells that were already dormantly infected with HIV would just die off on their own over time. If no new dormant, infected cells were created, they theorized the chronic HIV infection would eventually be eliminated.
The challenge of this or any approach to truly "curing" the disease is that virtually every latently infected cell must eventually die without a single new copy of virus being allowed to infect another cell. That's a pretty tall order and to date, no one has even come close to achieving it.
In the study reported in the August issue of The Lancet, a reduction of the number of latently infected cells, ranging from 68-85% in three of the four volunteers, was observed, while there was no response in the fourth volunteer. Researchers concluded that that this could be proof of the concept that we might someday be able to cure the disease. Dr. Margolis said that he was concerned that people might over-interpret these results as meaning a cure had been found, but he defended the belief that this was a step in that direction. Some scientists and many people living with HIV applauded the effort, while others raised caution because of the great challenge of dealing with virtually every infected cell.
While Project Inform is a staunch believer in the possibility and eventuality of a cure for AIDS, it's not clear that it's going to happen through eradication schemes of this nature. Others have done similar experiments, such as Roger Pomerantz at Thomas Jefferson University. He had similar results and a few patients remained virus free afterwards, without treatment, for several months. But eventually virus levels returned to detectable, evidence that not all infected cells were destroyed. Another similar experiment, at the Aaron Diamond Research Center in New York, resulted in what may have been life-threatening complications in a patient due to the side effects of a high a dose of the drug (OKT3) used for activating cells. Because the experiment failed and a patient was endangered, this experiment did not continue. Researchers in Dr. Anthony Fauci's lab at the National Institute of Allergy and Infectious Diseases also attempted eradication with a combination of anti-HIV drugs and IL-2 (interleukin-2, Proleukin), a potent immune stimulator. Although viral expression was completely suppressed in a number of people, without further treatment, for a number of months, HIV eventually reappeared. This proved that some latently infected cells had escaped the process.
It was refreshing in this new case that some scientists were able to see the results as a sign of progress rather than failure. Research of this type should definitely continue, even it has not yet been fully successful. It may be that multiple rounds of the process need to be repeated to achieve success or a longer period of treatment. Or perhaps we need to try a combination of activating the latently infected cells plus the new approach demonstrated by Dr. Margolis. One thing is clear though and it is that the mere use of standard anti-HIV drugs is unlikely to cure AIDS. One way or another, the problem of the reservoir of latently infected cells must be addressed. We applaud Dr. Margolis and his team for continuing this kind of research, even if we feel The Lancet may have engaged in a bit of unhelpful hype on the magazine's cover.