21 December 2010
Hints of a cure—the future of stem cell transplants and HIV
In 2008 a team of cancer researchers from Berlin, Germany, reported an important result—an HIV-positive patient with leukemia was treated with a unique stem cell transplant and not only did he recover from leukemia but researchers could no longer detect HIV in his blood samples.
In December 2010, further analyses from this man, dubbed the “Berlin patient,” became available. In these analyses the German team is still unable to detect HIV in his blood and now also his tissues, and the researchers suggest that he may be cured.
Although these results are extremely promising for the Berlin patient, because of several issues (explained later in this report) stem cell transplant technology available today will not result in curing HIV infection for most people. The good news is that the German results uncover an exciting avenue for research that might one day lead to better therapies, stronger immune systems and possibly a cure for HIV-positive people. Attempts to repeat the success of the Berlin patient are planned or underway in Western Europe and Israel.
In February 2007, a 40-year-old man, HIV positive for 10 years, sought care at Berlin’s Charité University medical centre because of a diagnosis of leukemia. For four years prior to his leukemia diagnosis he had been taking the following medicines for HIV infection:
- efavirenz (Sustiva and in Atripla) 600 mg/day
- FTC (emtricitabine, Emtriva) 200 mg/day
- tenofovir (Viread and in Truvada and Atripla) 300 mg/day
His CD4+ count was 415 cells and his viral load was less than 50 copies/ml.
The man received chemotherapy and developed severe liver and kidney toxicity. As a result, his doctors discontinued highly active antiretroviral therapy (HAART) but then his viral load became very high—nearly 7 million copies/ml. Stunned by this immense increase in viral load, his doctors reinstated HAART and within three months his viral load fell to less than 50 copies/ml and the leukemia went into remission.
A rare mutation
Seven months after the man’s initial leukemia diagnosis, the cancer returned. This time, his doctors proposed a bone marrow transplant. The donor of the bone marrow not only had a similar genetic makeup to the man, but he also had a rare genetic mutation that affected his immune system. The mutation, referred to by scientists as delta-32, resulted in the donor’s cells missing one of the proteins or receptors that HIV needs to enter and infect a cell. This receptor is called CCR5. The delta-32 mutation carried by the blood donor is extremely rare, found in about 1% of people of northern European ancestry. This rare delta-32 mutation is perhaps the most important aspect of the German report, and in the next section we explain why.
Know your receptors
HIV needs at least two receptors to enter and infect a cell. The first receptor is CD4+, which is found on many immune system cells. HIV usually then needs one of two other co-receptors, either CCR5 or CXCR4.
Some strains of HIV prefer to use CCR5, others CXCR4, and still others use both co-receptors. The bone marrow donor had the delta-32 mutation, and so his immune system lacked CCR5 receptors. Because the lack of CCR5 receptors makes cells somewhat resistant to HIV infection, the Berlin patient’s doctors hoped that a transfusion of stem cells from the donor would eventually transform and give rise to a fresh immune system for him that was at least partially resistant to HIV.
Preparing for the stem cells
The Berlin patient’s body was subjected to intensive chemotherapy for several days, and then he was blasted with radiation. In addition, doctors infused antibodies that attacked his immune system. As if that was not enough, they gave him several transplant drugs—including cyclosporine—all in an attempt to further weaken his immune system. The reason for such an intensive attack on his immune system was to allow the stem cells that he would subsequently receive to survive assaults by the remnants of his immune system. As his old immune system died, the doctors hoped that the transplanted stem cells would behave as if they were his and occupy the bone marrow and begin to divide, transform and mature into the many types of cells needed by the immune system.
Thirteen days after infusing him with stem cells, doctors confirmed that the transplanted cells had adapted to their new host and were beginning to rejuvenate his immune system.
The battle within
Sometimes a complication of transplantation called graft versus host disease (GvHD) occurs when cells from the donor attack the host’s body. Organs commonly attacked in GvHD include the skin, liver and intestines.
In the case of the Berlin patient, doctors stated that he only had mild skin damage from GvHD, presumably because they administered several immune-suppressing drugs as follows:
- cyclosporine (Sandimmune, Neoral)
- Cellcept (mycophenolate mofetil)
The effects of chemotherapy, radiation and additional immunosuppressive drugs can weaken both the remnants of the old immune system and the emerging new immune system. Life-threatening infections and other complications can consequently occur. Fortunately, the Berlin patient was spared these.
Relapse and recovery
Thirteen months after transplantation, the Berlin patient’s leukemia recurred and he again received chemotherapy and radiation followed by another infusion of stem cells from the same donor. He recovered from leukemia and remains in remission three and a half years after his transplant.
About a year and half after his first transplant, the Berlin patient experienced several neurologic problems suggestive of a brain infection called leukoencephalopathy. This can be caused by JC virus, which is commonly found in humans. JC virus can cause complications in people whose immune systems are severely weakened, such as those with AIDS or who are taking transplant medicines. Infection with JC virus damages the insulating sheath that covers nerve cells. Because the layer of insulation has degraded, signals sent by nerves can leak and become weakened. As a result, muscle control becomes difficult, speech and vision become impaired and even personality changes can occur.
MRI scans of the man’s brain suggested inflammation perhaps caused by JC virus infection, so surgeons removed a small amount of brain tissue for analysis. However, they could not detect any JC virus and proposed that his symptoms were caused by the toxicity of so much chemotherapy and radiation. Such problems can occur even months after chemotherapy or radiation have ceased.
The man’s neurologic symptoms spontaneously cleared and three years after his initial transplant, his doctors discontinued giving him immune-suppressing drugs. No GvHD has recurred.
What happened to HIV and his immune system?
Only about 2% of the body’s lymphocytes are found in the blood. Most of these cells are in the lymph nodes and lymph tissues scattered around the intestines. So, most HIV in the body is also found in these lymph nodes and tissues.
But lymphocytes are not the only cells attacked by HIV. Macrophages, another important group of cells, also have CD4+ and other receptors used by HIV to infect them. Macrophages are particularly important because, unlike T-cells, they can live longer even though they may become infected with HIV. Moreover, infected macrophages can rove throughout the body, entering and leaving organs and spreading HIV in the process. Some macrophages even become specialized and take up residence within certain organs, such as the brain, liver, bone marrow and so on, where they guard against infections.
Researchers took samples of tissue from the man’s brain, bone marrow, liver and intestines to find cells of the immune system and assess them for the presence of HIV. However, they could not detect any infected cells or HIV in the man’s tissues or blood. The Berlin researchers are not certain why HIV did not rebound after the stem cell transplant.
The stem cell transplant has not rendered the man entirely immune from HIV infection should he be exposed in the future. He will therefore need to practice safer sex.
In lab experiments done after transplantation, cells from the man’s new immune system remain susceptible to HIV. Specifically, the researchers added HIV to cultures of CD4+ cells from the man. Only HIV that uses the co-receptor CXCR4 to gain entry to cells is able to cause infection because the man’s new immune system does not have CCR5 co-receptors.
Biopsies of lymph tissues from his intestines suggest that the stem cell transplant has helped to form a new immune system. His CD4+ cell count in the blood is now about 800 cells—within the normal range. Although doctors in Berlin are unable to find HIV in the man, he continues to have antibodies against this virus in his blood.
A summary of his course
An HIV-positive man on HAART survived several bouts of chemotherapy, radiation and leukemia. Major risks of chemotherapy, radiation and other immunosuppressive therapy include life-threatening infections and bleeding. In the short-term, nausea, vomiting, fatigue and hair loss can also occur. Long-term complications from immunosuppressive therapy include damage to the liver, lungs, kidneys and heart as well as the formation of new cancers. Despite all of this, the man’s leukemia is currently in remission.
He received a stem cell transplant from an HIV-negative donor who had a rare mutation—the absence of a co-receptor called CCR5, used by HIV to infect cells. This mutation is also called delta-32 by researchers and makes it difficult for some strains of HIV to infect cells. The delta-32 mutation is generally rare, and even among people of northern European ancestry who are most likely to have this mutation, only about 1% do.
The man’s immune system has returned to normal throughout his body and his CD4+ cell count is within the normal range. Doctors are unable to isolate HIV from several tissues and organs and suggest that he may be cured of HIV.
Short-term implications of the Berlin study
The findings from the Berlin patient are extraordinary and deserve pause for thought. For the first time it seems that HIV can be cured.
It is still possible that deep within the man’s body there is a very small amount of HIV that can be controlled by his immune system. This possibility exists because the gold standard labour-intensive and time-consuming laboratory procedures that were done by other researchers when investigating past suggestions of a cure (with different therapies) have not been conducted.
Unfortunately, because the delta-32 mutation that confers resistance to HIV is so rare, finding a genetically matched stem cell donor for most other HIV-positive people is highly unlikely. Indeed, so far, preliminary searches within European stem cell registries for more potential donors that can be genetically matched to HIV-positive patients with cancer have yielded only a handful of potential donors. So, using stem cell transplantation as a potential cure for HIV cannot be generally implemented even in high-income countries.
The good news is that the developments in Berlin have stimulated the imagination of scientists both inside and outside of the field of AIDS research. Some researchers are designing genetic therapies to make stem cells resistant to HIV infection by a number of means. Preliminary results suggest that such therapies are safe, at least in a very small number of volunteers who have received them. The issue of safety is important for genetic therapies because in past experiments gene therapies can sometimes stimulate the formation of tumours. The Berlin doctors are also encouraging the use of the anti-HIV drug maraviroc (Celsentri, Selzentry) in future stem cell transplantation experiments with HIV-positive people. Maraviroc covers the CCR5 receptor on cells and has anti-inflammatory activity; both of these properties may be useful in future experiments with stem cell transplants in HIV infection.
Repeating the experiment
It is essential that the researchers at Charité University and elsewhere attempt to repeat the results obtained with the Berlin patient. To this end, the Berlin team has obtained agreement from leading European stem cell registries to support further experiments. Stem cell transplants with the delta-32 mutation in HIV-positive people with cancer are now planned or underway in at least nine people in Western Europe and Israel. In part, the reason for this low number is that the delta-32 mutation is so rare.
Some researchers are designing genetic therapies to make stem cells resistant to HIV infection by a number of means. Preliminary results suggest that such therapies are safe, at least in a very small number of volunteers who have received them with several years of monitoring. The issue of safety is important for both stem cell transplants and genetic therapies because in past experiments gene therapy can sometimes inadvertently trigger the formation of tumours. Here are some issues to bear in mind with such therapies:
- In the medium-term, experiments with stem cell transplants and gene therapy attempting to renew the immune system will likely be tested in HIV-positive people with leukemia or lymphoma, as such people have the greatest need for stem cell transplants.
- Long-term monitoring of HIV-positive people who receive stem cell transplants together with genetic therapy to render the CCR5 co-receptor absent are needed. This need arises not only to be sure that there is no increased risk for cancer but also because no one knows the potential long-term toxicity of grafting a CCR5-deficient immune system in someone who has previously had CCR5 receptors in his/her immune system.
- Will intensive chemo- and radiation therapy always be needed for HIV-resistant stem cell transplants to be effective in their new hosts? Such therapy carries a risk of severe and life-threatening complications. Already one young HIV-positive person had died in Israel after an attempted stem cell transplant. Stem cell transplants are not usually done in people over the age of 60. Can this barrier be overcome?
In the next decade, as scientists gain more experience with making stem cells resistant to HIV infection, expect to hear more reports about the use of stem cell therapies to rebuild the immune systems of HIV-positive people. Hopefully, such reports will also include news about curing HIV infection.
—Sean R. Hosein
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