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Project Inform Analysis: Results of a "Cure" Study

August 2005

The August 12 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. Unfortunately, the magazine splashed the word "CURE" all over the cover and raised inappropriate expectations about what the study was able to accomplish.

The approach described in the article was proposed and discussed in the Project Inform Immune Restoration Think Tank several years ago. It was proposed at that time by David Margolis, whose lab managed the study mentioned here. The basic 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 Institute of Medicine. Project Inform has described this potential approach to a cure in a number of articles over the years.

The basic idea is to provide maximal suppression of viral replication by whatever means available. In this case, they started with 4 people whose viral load was "undetectable" to begin with, then intensified their standard treatment with the addition of T-20. Next step is to use one or another available drug to activate the reservoir of latently infected cells. In this experiment, they used a substance called valproic acid, though there are other substances which have also been tried. These latently infected cells are normally not affected by antiviral drugs because they are inactive and not producing virus. Thus, the antiviral drugs have nothing to do. Antiviral drugs can only work with cells that are active and producing new copies of virus. Additionally, when cells are inactive, they are not recognized by the immune system, 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.

When another type of drug is given to activate the latently infected cells, they begin to produce copies of virus. This makes them visible to the immune system. The hope is that the regular antiviral medications will stop any virus that is produced from the newly activated cells and that the immune system will then be able recognize these cells and destroy them because they are producing virus. It's a perfectly logical theory.

The limitation though is that it will only "cure" the disease if absolutely every latently infected cell is activated and subsequently killed by the immune system, and that every new copy of virus made by the activated cells gets stopped in its tracks before it can go on to infect a single other cell. That's a pretty tall order and to date, no one has even come close to achieving it.

In this particular study, they reported a reduction of the number of latently infected cells by 68% to 85% in three of the four patients, while there was no response in the fourth patient. They concluded that that this might be proof that we might someday be able to cure the disease.

While I'm a believer in the "cure," I'm not sure this is the way it's going to happen. Others have done similar experiments before, 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 returned evidence that not all infected cells were destroyed. Another similar experiment, done without publicity 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 was never publicly discussed or disclosed. A few others have also tried this "activation" approach to a cure without success. Experiments which fail are seldom published, so we don't necessarily learn much from them. It was refreshing in this new case that they were able to see the results as a sign of progress rather than failure.

Research of this type should continue, even if it has not yet been fully successful. It maybe that multiple rounds of the process needed to be repeated to achieve success, or perhaps we have yet to find the ideal drug for activating the latently infected cells. One thing is clear though and it is that the mere use of standard antiviral drugs will never cure the disease. 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.

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