AIDS Cure Goes from Crackpot Notion to 'Which Kind of Cure?'
By Anette Breindl
Until quite recently, if you talked about a cure, AIDS researchers assumed you were either a fool or an ACT UP activist. Now, three patients appear to have been cured.
One is no longer taking medication for his HIV infection. The other two patients, whose cases were presented at the XIX International AIDS Conference last week, are still on antiretroviral drugs. But in all three, no trace of virus can be found in their cells, two to five years after they received bone marrow transplants for leukemia.
And scientists are not only discussing the general possibility of a cure, but distinguishing between two types of cure: functional and eradication cures.
A functional cure, David Margolis told BioWorld Today, means that virus remains undetectable in the absence of antiretroviral treatment, as they are with the first cured AIDS patient, Berlin patient Timothy Brown.
What is unclear is whether Brown has had an eradication cure, that is, whether the virus is truly gone from his body or still hiding out in latent reservoirs where it is not dividing, but possibly ready to start doing so again when conditions are right. Distinguishing between a functional and an eradication cure may seem like arguing about whether a large starving population should be fed with shrimp or steak when neither is available. But Margolis, who is at the University of North Carolina at Chapel Hill, said that at least for HIV patients in the developed world, the distinction is not trivial. In fact, "I want to cure AIDS for different reasons than people with HIV want to be cured."
From his perspective, having people on a lifelong, complicated therapeutic regimen is burdensome for the patients and costly for society.
But "patients want a cure because they don't want to be different from the rest of society anymore." And that goal can only be achieved with an eradication cure. Functionally cured HIV-positive patients could still be infective, which marks them as different from others and necessitates continued precautions against infecting others. And so, patients far prefer the notion of an eradication cure, and are "less willing to undergo treatment and take risks" for a functional cure than for an eradication one.
For an eradication cure, those reservoirs somehow have to be brought to the attention of the host immune system. In the June 26, 2012, issue of Nature, senior author Margolis and his colleagues described a strategy that could achieve that goal.
In their studies, Margolis and his team treated eight HIV patients, who remained on antiretroviral treatment, with the HDAC inhibitor Zolinza (vorinostat, Merck and Co. Inc.). When they looked at resting T cells that is, T cells that were not actively engaged in fighting an infection from those patients after the treatment, each of the eight showed an increase in HIV RNA, meaning that the drug had induced translation.
Margolis stressed that although his team induced transcription of the virus, they specifically did not do so by activating the T cells. That approach, in the form of antiretroviral treatment plus stimulation of CD3 receptors, was attempted about a decade ago, and Margolis summed up the results as "a disaster."
He also stressed that many unknowns remain about the approach. "A single dose broke latency," he said. But what is still unclear is how long the cells come out of latency, and whether there is translation, that is, the production of viral proteins. Most importantly, at present it is unknown whether the immune system notices or cares when latency is broken by that approach. "We don't know whether some, or none, or all of the cells are cleared because we have induced expression of the virus."
Even if breaking latency alone is not enough to induce clearance of infected cells, the next possibility would be to combine it with a therapeutic vaccine. Margolis said that "there is a large body of vaccine work that is directly applicable" to such an attempt.
In Margolis' opinion, it is ultimately "easier to conceive of eradication therapy than of a highly effective [preventive] vaccine," though he cheerfully acknowledged that his opinion just might be related to the fact that he is working on an eradication cure. And he also acknowledged that it doesn't really matter which one is more difficult. "Both are very difficult to do," he said, "and both have to be done."
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