BOSTON—A 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 molecule—the 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-32–carrying 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.
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.