The notion of introducing genetic alterations in human cells to enable them to repel the HIV virus has been around for a long time. A new study was reported in today’s issue of the New England Journal of Medicine, showing moderate success in doing just that. The idea is called “gene editing” – a process by which a specific gene is modified in order to confer a protective function on the cells that carry the modified genetic material.
Fairly early on in the history of the AIDS epidemic, researchers had identified a class of patients called “Long Term Non-Progressors” (LNTPs): these were patients who were infected by the AIDS virus, and who were serologically positive for HIV infection, but who often went for years without the need for anti-retroviral therapy, and also without developing symptoms of the illness. Upon examination, some LNTPs were found to have a special version of a molecule on their T-cells (called CCR5-delta-32 polymorphism) that made the cells resistant to invasion by the virus.
In a very famous recent case, a man known as the “Berlin patient” who suffered from leukemia as well as AIDS, had his bone marrow totally destroyed by irradiation, and then replaced with bone marrow from a donor who had two copies of the CCR5-delta32 polymorphism, in 2007 and 2008. He thus became the very first person ever declared “cured” of HIV infection – his immune system rebounded, and he was able to discontinue anti-retroviral therapy. Several years later, there was still no sign of HIV infection in his body. This fact suggested a possible avenue of treatment. Eradication of a patient’s bone marrow – especially in someone who is immuno-compromised – is tremendously dangerous. Might it be possible instead to take just the T-cells from an HIV-infected patient, and change the CCR5 molecule on the surface of their cells to the protective CCR5-D32 version?
In the study reported on today, researchers used a process called “ex vivo manipulation” to do just that (ex vivo is Latin for “outside the body”). 12 people infected with HIV had their T-cells removed, which were then genetically engineered in the lab to equip the cells with the protective gene, and then replaced in the bloodstream intravenously. The hope was that if sufficient numbers of T-cells are gene-edited in this way, the patients would be able to completely repel the HIV virus. The 12 patients received infusions of 10 billion of their own CD4 T-cells, modified to carry the CCR5-modified version of the T-cell receptor. The technique successfully disabled the CCR5 gene in 11 percent to 28 percent of the engineered cells. After four weeks, six patients interrupted their anti-retroviral treatments. In most patients, their HIV levels increased and their immune cells declined. The modified immune cells, however, declined less precipitously than the patients’ unmodified cells, suggesting the gene-editing had had a protective function. The altered cells also persisted for a while: on average, after 48 weeks, half of the modified immune cells were still present.
This experiment was made possible by the recent development of a technology for altering the genetic material of a cell. “Zinc-finger nucleases” are a molecular power-tool: enzymes capable of cutting DNA at very specific sites. The potential of these enzymes was originally tested in mice. The success of these animal models encouraged the researchers to expand their use into clinical trials in humans.
Clinical trials begin with a study of safety, rather than efficacy. This particular pilot study did establish that immune cells could be altered, and that no harm came to the patients, other than one patient who reported a brief spell of fever, chills and joint and back pain. Further trials will be required to establish how effective the gene editing technique is, before the technique becomes available for widespread use.
Dr. Carl June of the University of Pennsylvania, the senior author of the study, explained some the advantages of this approach to HIV treatment. Many patients find the anti-retroviral drugs carry unpleasant side-effects, and require expensive, life-long treatment. Future goals for the researchers will be to increase the proportion of T-cells that are changed to carry the protective gene, and to find ways to make them last longer in the body. A phase II clinical trial will have to be done to establish that the treatment can be made practical for large numbers of patients. According to the rules for experimentation on humans that changes their DNA, the Food and Drug Administration requires that the patients be monitored for 15 years to ensure no adverse effects. Some previous experiments that involved modification of human genetic material were documented to have inadvertently triggered oncogenic (i.e. cancer-causing) mutations, although the current study has seen no evidence of that so far. Thus, the notion that HIV in infected patients may be repelled by gene editing has been established and merits further development.
By Laura Prendergast