The treatment that cured Brown of his HIV and cancer has some devastating potential downsides, however. For one, transplanted donor cells can be rejected just like a donor heart, putting the patient at risk of disease and often requiring powerful immune suppressants, with all the attendant side effects and risks. With the current AIDS drug cocktail so effective, such dangers would be unacceptable unless, as with Brown, the patient needs bone marrow therapy anyway.
Building on Brown’s amazing recovery but hoping to avoid the pitfalls, AIDS researchers are devising treatments based on the patient’s own tissue, which would not be subject to rejection like donor cells. One of the most promising approaches uses a new type of genetic scissors known as zinc finger nucleases, developed by California-based Sangamo Biosciences. These finger-shaped proteins form when specific amino acids (protein building blocks) bind to a charged zinc atom. They can be engineered to go into cells and snip any gene a researcher wishes to target (including the gene for the T-cell receptor CCR5). The damaged cells automatically set about repairing the cut, yet 25 percent of the time that effort fails, and the deleted gene is never restored. Such cells can be separated out, creating a pool of HIV-resistant cells lacking CCR5. These lab-engineered cells can then be amplified and grown out a hundredfold or more before being infused back in. They are safer than cells transplanted from a donor because risk of rejection is gone.
The first human trials testing genetically engineered cells missing the CCR5 receptor, begun in 2009, have been small but impressive. At Quest Clinical Research, Lalezari enrolled nine men on the cocktail with persistently low CD4 counts who were HIV positive for 20 years or more. The genetically engineered cells survived after infusion, and CD4 counts went up in five of six patients he has reported on, including Matt Sharp. “The ratio of two types of immune cells, CD4 and CD8, which are often abnormally reversed in HIV, normalized, and the HIV-resistant cells even migrated to the gut mucosa, an important site for the virus,” Lalezari says. “The results were as good as I could possibly have hoped for.” Though his approach is distinctly different from a donor stem cell transplant like Timothy Brown’s—in which the entire immune system is replaced—it is a promising start, with potentially significant clinical benefit and far less risk.
A similar trial launched in 2009 by pathologist Carl June and internist Pablo Tebas at the University of Pennsylvania has shown equal promise. Here, six patients suspended combination antiretroviral therapy for 12 weeks after infusion with altered CD4 cells, so scientists could monitor viral load and the power of the altered immune cells to survive and thrive in the presence of active HIV. At present, two of the patients have been fully studied. In one patient, the virus took 10 weeks to rebound instead of
the usual two to four weeks. In the other patient, the virus was still undetectable 12 weeks out. The next step is to increase the percentage of genetically engineered cells, either by increasing the amount of cells in the infusion, by giving more than one infusion, or by administering chemotherapy to lower the number of untreated CD4 cells in the body before infusion begins. Other researchers plan to try this approach on patients who recently received a diagnosis of HIV and are not yet on antiretroviral therapy. “It sounds like science fiction, I know, as if I just told you people landed here from Mars,” Tebas says. “That’s how far the technology has evolved.”
The most viable form of this treatment might be to target progenitor cells giving rise to CD4 cells and the rest of the immune system—stem cells themselves. If some of those cells could be removed from a person with AIDS, genetically engineered to be resistant, and then returned to the patient, they might spawn an immune system that is completely resistant to the disease. The virus could actually help, since it would continue infecting and killing unchanged, vulnerable cells—decimating its own resources in the process.
A stem cell transplant like this has already been accomplished in mice by virologist Paula Cannon of the University of Southern California. Cannon used a special strain of mouse that lacks a functioning immune system and so can be given human immune cells without rejecting them. Mice were infused with human stem cells, half of them genetically engineered so that the CCR5 receptor was gone. After 8 to 12 weeks, the modified cells had increased in number, effectively resisting infection with—and controlling replication of—HIV.
“These mice are a real breakthrough for HIV research,” Cannon says. “But now we need to find the sweet spot, the Goldilocks spot, where we can alter enough stem cells to allow someone to live with HIV.
Ultimately an anti-AIDS stem cell transplant might look like this: You would have your stem cells withdrawn and genetically altered to resist HIV. Simultaneously, you would get a mild form of chemotherapy to wipe out some of your remaining vulnerable stem cells. Then you would get an injection of the new stem cells. They would proliferate rapidly and create a resistant immune system. This immune system, especially the CD4 T cells, would have an advantage because HIV could never invade or kill them, and over time, they would become dominant.
Some researchers are optimistic that stem cell therapies might be able to deliver what researchers call a functional cure: Patients would achieve a state of remission in which the viral load was less than 50 copies of HIV per milliliter of blood, undetectable on standard tests, and they would no longer require medication. “This therapy isn’t about eliminating every last HIV from the body. It’s about giving the body the tools to stay well when the reservoir wakes up,” Cannon states. “If people can have this treatment, not have to take HIV drugs, not have detectable levels of the virus, and have a fully functioning, happy immune system, isn’t that good enough?”
Not for David Margolis, an AIDS researcher at the University of North Carolina at Chapel Hill. When the virus lurks in latent reservoirs in the body, he says, there are consequences for patients’ health. “You’re not going to cure HIV this way. It’s a giant technological problem as difficult as inventing a warp drive to travel to other stars. Unless you go in and kill all the stem cells that make CCR5, there will always be cells that the virus can grow in. You may lower the load, you may even prevent disease progression and eliminate need for antiretrovirals, but you will still have chronic immune activation and the problems caused by that.”