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New Hope for a Cure

Spring 2011

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New Hope for a Cure
Since the earliest days of the epidemic, people have hoped for a cure and a vaccine. In 1984, when the discovery of HIV was confirmed, then-Secretary of Health and Human Services Margaret Heckler famously announced that a vaccine would be ready for testing within two years. Over 27 years later, we're still waiting. Likewise, David Ho estimated in 1996 that highly active antiretroviral therapy (HAART) could eradicate HIV from a person's body after two years -- a cure. As many suspected, that was somewhat optimistic -- the actual time on HAART needed to rid the body of all HIV has been estimated to be as long as ... 78 years!


Eradication

The reason? Well, we now know that HIV "seeds" certain reservoirs in the body very soon after infection: the gut, brain, genital tract, and an important part of the immune system known as "resting memory CD4 cells." These cells have been a particular target of cure research. Unlike most CD4 cells, which live only a week, memory CD4 cells live for decades. They do this by shutting down -- going into hibernation -- to be reactivated only when the infection they were created for reoccurs. HIV infects about one in a million memory CD4 cells, and attempts to purge them of HIV have so far proven futile. But efforts are continuing. Over 20 HDAC inhibitors (cancer drugs that may be able to activate the latent virus in these cells) are being studied. IL-7, a growth factor found in the body, can activate cells and is moving forward into clinical studies. There has even been talk of destroying all these cells, but that would wipe out all the "immune memory" a person has spent a lifetime building, It also wouldn't solve the problem, since there are other places in the body HIV can hide, and other cells (dendritic cells, monocytes, macrophages, etc.) that act as reservoirs.

The good news is that the low-level replication in these reservoirs usually does not create resistant virus if a person's viral load remains undetectable. The bad news is that HIV is still there and once HAART is stopped, viral loads quickly rebound.


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The First Cure

So the possibility of finding a treatment than could eliminate every particle of HIV from the body remains slim. Hopes for a cure got a boost in 2008, however, when researchers reported on Timothy Brown, the "Berlin Patient." He had failed treatment for leukemia, so a risky bone marrow transplant was attempted. But instead of searching only for a bone marrow match, scientists looked for a donor who also had the "delta 32" mutation. It was discovered in the early 1990s that some people have a natural mutation that eliminates a receptor HIV uses to enter cells: the R5 receptor. Studying these rare individuals led to the development of Selzentry, which blocks R5. But Tim's case was different -- an attempt to replace his CD4 cells with ones that completely lacked the R5 receptor.

Happily, it seems to have worked. Four years after the treatment, researchers can find no trace of HIV in Tim's body, even using the most sensitive tests. So it appears that at least one person has been cured of HIV. Unfortunately, the treatment used is not only life-threatening, it's also expensive -- about $250,000.

Could there be other ways to achieve a cure? That depends on how you define "cure." In his regular updates on the possibility of a cure, Dr. Anthony Fauci, head of NIAID, talks about the search for both a "sterilizing cure" and a "functional cure." The former refers to the removal of all HIV from the body -- something Fauci thinks is unlikely in the near future without a major scientific breakthrough. But the latter is something we may live to see. A treatment for a functional cure would "reprogram" the immune system to control HIV without any medication. We know there are people who can do this (long-term nonprogressors) and they are being studied by Bruce Walker in the International HIV Controllers Study (hivcontrollers.org).

It's actually quite common for the immune system to rely on a functional cure when a systemic cure is not possible. For example, varicella zoster virus, which causes chickenpox, is never eliminated from the body. It remains in the spinal fluid for life, but a healthy immune system can control it. This is the case for many pathogens. In fact, if all the microbes in the body are counted, 90% of them are not human. An incredible number of bacteria, viruses and other pathogens take up permanent residence in the human body as soon as someone is born. We just live with them. Could there be a way to do the same thing for HIV?


Recent Efforts

Just recently, two studies presented at the 18th Conference on Retroviruses and Opportunistic Infections (CROI) in Boston presented treatments that may be able to do just that. Both used gene therapy, a process in which a portion of a person's blood is removed and CD4 cells are separated out and modified by treating them with a "zinc finger" nuclease that blocks the R5 or X4 receptors. With a now changed set of genes, the CD4 cells are reinfused within 20-30 minutes. Two investigators reported using this technology, the first being Jay Lalezari of Quest Clinical Research in San Francisco, and the second Craig Wilen of the University of Pennsylvania.

New Hope for a Cure

In the Lalezari study, six men who had CD4 counts between 200 and 500 (despite having been on HAART for at least two years with undetectable viral loads) received the gene therapy SB-728T. After having had their blood removed and treated with the drug, five of the six men responded well to the modified CD4 cells. They had an average CD4 count increase of 200 just two weeks after receiving the infusion, and sustained it for a year without any further infusions. The great news is that for some, CD4 counts increased by as much as a 1,000 and that a year later, the increase was still over 900. All of the men tolerated the infusion well, without any serious side effects. Some less serious side effects included chills, fever, headache, sweats, dizziness, fatigue, and a short-lived "garlic" body odor. All of these were easily managed. One man did not respond, which the researchers think may be due to his lower CD4 count before receiving the infusion.

When the investigators looked closely at what effect the infusion had, they found that 25% of the reinfused cells had no CCR5 receptor, and after three months, up to 6% were still missing the receptor. It also appears that the modified cells reached many different parts of the body, including the gut. This suggests that a single infusion may lead to a supply of modified CD4 cells lasting at least a year if not longer.

The trial is continuing and will look at the effect of gene therapy on several groups of people. Jay Lalezari at UCLA will study as many as 21 people with less than 500 CD4 cells who have never been on HAART therapy respond to the gene therapy. Trials will also expand to include a total of 18 participants in Philadelphia and New York City in the upcoming months. These studies will look at how the therapy works in three groups:

  • People who have not responded to HAART (viral loads over 2,000 and CD4 counts above 200)
  • People who have responded to HAART and have undetectable viral loads
  • People who have responded to HAART, but have CD4 counts below 500
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This article was provided by ACRIA and GMHC. It is a part of the publication Achieve. Visit ACRIA's website and GMHC's website to find out more about their activities, publications and services.
 

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