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Promising signs emerging from HIV gene therapy trials

blood2.jpgResults continue to trickle out from two clinical studies of an innovative HIV treatment, in which a subset of patient immune cells are extracted from the blood, genetically modified to make them resistant to HIV and injected back into the patient. Carl June, at the University of Pennsylvania School of Medicine in Philadelphia, where one of the trials is being conducted, presented data from the first two years at a small meeting of experts outside of Philadelphia hosted by the Foundation for AIDS Research (amfAR).

Around nine patients have completed the trials at UPenn and at the University of California in Los Angeles without any severe adverse events. And counts of CD4+ T cells, both natural and genetically altered, have gone up in all but one patient and migrated to gut mucosa. Although he could not yet speak about levels of virus in the blood for all patients, he said that their results “suggest there’s an antiviral effect”, even when antiretroviral treatment was temporarily halted for a small number of patients.


Sangamo, the company that developed the treatment, has said that more results will be presented at the Interscience Conference on Antimicrobial Agents and Chemotherapy this coming weekend. Although primarily designed to assess safety and feasibility of the treatment, the Phase I trials, coupled with results from other basic and animal studies, have several AIDS experts talking tentatively about the possibility of a cure for the disease, something that scientists and clinicians have avoided since disappointments in the mid 1990s. “Cure has been a four letter word,” says Steven Deeks, a clinical researcher at the University of California, San Francisco, who has patients enrolled in one of the trials.

Much of the renewed excitement is due to the revelation in 2008 that someone infected with HIV had, by all current measures, been cleared of the disease. Timothy Brown, sometimes called the ‘Berlin Patient‘, was treated for leukaemia and required a bone marrow transplant, but doctors, recognizing an opportunity to try and treat both his cancer and his HIV, sought out a donor with a specific variant of CCR5, a cell surface receptor that HIV uses to gain entry into the cell. People with inactive CCR5 variants are highly resistant to most types of HIV infection. They found a donor, and Brown is now off antiretrovirals with no detectable virus levels.

Sangamo has been working to see if something similar can be achieved by modifying and transplanting a patient’s own cells. In the trial at UPenn, says June, patients were hooked up to an apheresis machine and white blood cells were removed from their blood. These were processed and treated with what are known as zinc finger nucleases, proteins designed by Sangamo to knock out part of the CCR5 gene in as many of the patient’s CD4+ T cells as possible.

There are differences between this approach and the treatment that Brown received, which some suspected would render it unsuccessful. Unlike Brown, the trial patients did not receive any sort of ablative therapy to kill off their existing, infected immune system prior to the transplant. Also, only T-cells, rather than bone marrow, were being given to the patient. So other cells, such as macrophages, may still harbour the virus. Finally, the genetic modification doesn’t hit every cell being injected into the patient. Some will carry only one mutated copy of CCR5, others might carry none. “I had been dubious of the Sangamo approach at first,” says Deeks.

But in addition to the promising Phase I results, he says, other data presented at the amfAR meeting suggest that it might not be necessary to kill off the patient’s immune system. Hans-Peter Kiem of the Fred Hutchinson Cancer Center in Seattle presented data on macaques that had used a similar procedure to make them resistant to a virus related to HIV. The animals were better protected from infection than untreated animals. And their data suggest that complete ablation may not be necessary because they saw that unmodified T cells were protected and able to expand after being challenged by infection.

Approval of a therapy like Sangamo’s will be years in the making, and the final product may look significantly different from the treatments they are currently testing. Gene therapy, says June, “is held to a higher standard than other treatments.” The amfAR meeting was held in part to discuss strategies for improving this kind of therapy — from using different cell types, to different vectors for modifying genes, to ways of expanding the cell population to be transplanted. The mood was upbeat, despite the many challenges and questions that remain about whether a cure is possible. “We still don’t know the mechanisms of how the Berlin patient worked,” says June. “We now have now a tool set to dissect [them].”

Image: Blood, from Andrew Mason via Flickr under creative commons.

Correction: amfAR is The Foundation for AIDS Research. Now appended.

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    Matthew Porteus said:

    The “Berlin” patient is a fascinating, but still anecdotal, use of bone marrow transplantation to potentially cure HIV. It would be extremely valuable to increase the number of patients treated this way to get a better sense of the robustness of the approach. The probability of finding an HIV patient with another disease for which bone marrow transplant can provide curative therapy AND has an immunologically matched donor AND that donor is homozygous delta32 is extremely low. An alternative approach would be to transplant HIV infected patients for that indication alone with an HLA matched sibling delta32 homozgyous donor. Based on delta32 allele frequencies, one would expect that ~0.3% of patients of Swedish or Russian origins to have such a donor. In a young patient one would expect the transplant related mortality to be ~5% and the risk of chronic graft vs. host disease to be 10-20% in this setting. The question is if one were a young (in your 20s) and had the option of this type of potentially, but not means proven, curative transplant vs. life long anti-retroviral therapy, would it be reasonable (ethically, medically, socially…) to choose to undergo a bone marrow transplant as part of a research protocol?

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