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10 Sientific stories of 2011- new HIV target
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2011-12-28
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Giving HIV a Poor Reception: New AIDS Treatment Tinkers with Immune Cell Genes

 

Researchers have found new ways to interfere with a co-receptor important to HIV infection, and the outcomes so far are encouraging

By Bob Roehr  | March 3, 2011 | 3


HIV and a CD-4 receptor

 

 

BOSTONA novel treatment for HIV could involve changing the genes in a person's immune cells and, ultimately, in his or her stem cells, as well. It might even lead to a cure for that deadly disease. Promising advances in that direction were presented here Monday at the 18th Conference on Retroviruses and Opportunistic Infections.

The pieces have been coming together for some time. First came the understanding that HIV enters a cell by grabbing on to a CD4 receptor molecule on the surface, and then on to a co-receptor moleculethe one most commonly used is called CCR5.

Then came discovery of the delta-32 mutation to the gene that encodes CCR5. Individuals who inherits a copy from one parent have fewer CCR5 receptors on their cells, are more resistant to becoming infected with HIV, and if infected, have a slower disease progression than a people without the mutation.

Inherit a mutant gene from both parents and the result is no CCR5 receptors at all, which makes it almost impossible for HIV to enter a cell. About 1 percent of Europeans have this double variant.

Pharmaceutical companies took this as a cue to develop a way to chemically block the CCR5 receptor, thereby artificially denying HIV entry into the cell. The result was the small molecule drug maraviroc, which has been on the market since 2007.

"The Berlin patient"
That same year, German researcher Gero Hütter was treating a patient on therapy for HIV infection who had developed acute myeloid leukemia. Treatment for leukemia involves effectively eradicating the immune system with radiation and chemotherapy, followed by a bone marrow transplant containing stem cells to build a new immune system.

He was intrigued by the possibility of using a bone marrow graft from a donor who carried the double CCR5 mutation. His patient, who would initially request anonymity and become known as the "Berlin Patient," embraced the experiment.

Good fortune was with them; among the German registry of donors who were a good HLA (human leukocyte antigen) tissue match to the patient (necessary to prevent transplant rejection), was a single donor with the rare CCR5 double mutation.

Treatment moved forward: A recurrence of the leukemia required a second round of radiation and chemotherapy, and then bone marrow transplantation of the CCR5 delta-32carrying stem cells. The new stem cells were given time to establish a new immune system before all anti-HIV drugs were stopped.

And nothing happened. Typically when a person with HIV stops therapy even undetectable virus quickly rebounds to very high levels, generally within a few weeks. The doctor and patient waited as the months ticked by, and still no virus reappeared. They came to the conclusion that they had proved their hypothesis; the patient had apparently been cured of HIV.

They avoided the glare of public disclosure throughout the experiment but finally were confident enough with the outcome to publish a paper on the case study in 2009 in The New England Journal of Medicine.

Zinc fingers
This proof of principle was intriguing but it was difficult to see how it might apply to more than a handful of patients.

One could not destroy a patient's immune system with radiation and chemotherapy unless there was a medically justified reason for doing so, such as treatment for cancer. Finding a compatible bone marrow match is difficult enough for many patients. Adding the requirement of the rare double CCR5 mutation exponentially multiplied the problem.

One possible option was to narrow the focus of research from stem cells and their pluripotent capacity to generate a broad array of cells to specific immune cells that are important to HIV. CD4+ T cells were the natural choice. These T cells express the CD4 receptor and are a key component of the immune system as well as the favorite target for HIV to infect and reproduce.


Sangamo BioSciences, a Richmond, Californiabased pharmaceutical company, has developed a "zinc fingers" technology that can home in on the CCR5 section of cellular DNA and artificially create a functional equivalent of the delta-32 mutation. They backed the study announced on Monday, along with the nonprofit California Institute for Regenerative Medicine, which was set up by the state in 2004 via a $3-billion bond issue to promote stem cell research.

This first-of-its-kind study involved six male patients aged 48 to 55 at the University of California in Los Angeles and San Francisco. All of them had been infected with HIV for 20 to 30 years but were on therapy and suppressing HIV below the level of detection. But those decades of infection had taken a toll; their CD4+ T-cell counts were between 200 and 500, less than half what is considered normal.

The study gathered circulating CD4+ T cells from the patient's blood via a process called apheresis. At a central processing facility, the cells were modified with the zinc finger process, then those that were successfully changed to carry the delta-32 mutation were expanded, or grown in very large numbers. Finally, 30 billion of them were infused back into the patient.

The results, which were part of a phase I safety study (rather than phase II efficacy study) were soon apparent. Study leader Jay Lalezari of Quest Clinical Research says there was "a significant engraftment and expansion of the cells, a three-fold increase over what would have been predicted." The total CD4+ T cell count increased by at least 100 in five of the six patients. The changes persisted, with 67 percent of cells showing the modification in the blood three months after treatment.

The researchers took myriad other measures during the study and all seemed to move in a positive direction. Lalezari says it is "probably as good as we could have hoped for in this population."

One subject's experience
Matt Sharp is a veteran HIV treatment activist who was concerned with his low CD4+ T cell count. It meant he had to take various drugs as prophylaxis to prevent the development of opportunistic infections. It also meant having to live with the side effects of those drugs. So, he chose to enroll in the zinc finger study.

He is pleased that his CD4+ T cell count roughly doubled to more than 500 and has remained there so far for six months. It meant he was able to discontinue the prophylaxis drugs.

Scott Hammer, an AIDS researcher at Columbia University's College of Physicians and Surgeons and a vice chair of the retroviral conference where the results were presented Monday, says, "This is early work that takes molecular biology into the clinic…. We shouldn't be raising the flag to say we've solved the problem yet."

Lalezari agreed, emphasizing that this is proof-of-concept study demonstrates that it is technically feasible to do the work, and it is safe. The procedure's real test will come when patients stop their therapies. Will the virus remain suppressed or will they have to go back on a drug regimen?

Another step that may be required for a "cure" is developing a parallel genetic "fix" for CXCR4, another co-receptor HIV sometimes uses to enter cells. And it may be that the modified CD4+ T cells will run their life course and have to be replenished periodically. Perhaps it would make sense to modify stem cells as a more permanent source of protection from HIV infection. That, however, raises another set of issues.

Sharp is wary about stopping his HIV drug regimen. He feels his immune system is fragile and is waiting to see how successful the treatment is for other patients who started the program with a higher CD4+ T cell counts. But he does look forward to the day when future developments might bring a cure and allow him to completely stop his HIV medications.