“In conclusion, our results strongly suggest that cure of HIV has been achieved in this patient.”
That is the incredible last sentence of the abstract from a new article in the journal Blood, the journal of the American Society of Hematology. The article is actually a follow up on a case report from over two years ago, when a patient who was HIV positive underwent treatment for acute myeloid leukemia (AML) by receiving total body irradiation and a bone marrow transplant from a specially selected donor. Over two years later, he has not taken any antiretroviral medication and the virus is still undetectable in his body.
Timothy Ray Brown, an American living in Germany, began chemotherapy for AML in 2006. The conventional chemotherapy regimen failed, so his physician, Dr. Gero Hütter, of Berlin's Charité Medical University, decided that it was time to begin the standard second line treatment – a bone marrow transplant. However, Dr. Hütter had a theory that he might be able to kill two birds with one stone. If the patient was going to receive a bone marrow transplant – completely destroying the patient's immune system and replacing it with a new one – why not transplant in a new immune system that's naturally resistant to HIV?
Dr. Hütter was aware of a genetic mutation on human CD4 T-cells (the immune cells that are attacked and destroyed by HIV) called CCR5-Delta 32. In most people, the 'normal' CCR5 gene makes a protein on the surface of the T-cell that HIV attaches to and enters the cell, allowing for replication and disease progression. People who have the CCR5-Delta 32 mutation produce a CCR5 protein that HIV has difficulty attaching to, leaving these patients essentially immune to HIV infection. The mutation is present in 1% of Europeans, but is very rare in Africans and Asians.
So when searching for a donor, Dr. Hütter kept an eye out for a match that had the CCR5-Delta 32 allele from both parents (each person has two copies of every gene, one from each parent. A CCR5-Delta 32 mutation on only one gene only delays HIV progresson). The search for a compatible bone marrow donor yielded 80 people in Germany that matched his profile, and the 61st donor provided the desired mutation. Brown underwent the standard procedure for a bone marrow transplant, receiving drugs and whole body irradiation to kill off his own immune system. He stopped taking his antiretroviral HIV drugs when he received the transplant so the antiretroviral HIV drugs wouldn't harm the new donor cells, with plans to resume them when HIV resurfaced. However, the HIV never returned. Tests on Brown's blood show no traces of the virus, nor in the brain, liver, spinal fluid, and rectal tissues where HIV can hide and lay dormant. His new immune system has 'taken' completely, and is genetically identical to his CCR5-Delta 32 donor, with no trace of Brown's old immune system.
So two years after this procedure, Brown is functionally cured...he used to be infected with HIV, and now there's no trace of the virus in his body at all, something that has never been seen before. But what does this mean for everyone else with the disease? Many experts are quick to point out that while this is an important medical milestone, it is far from a viable option to treat HIV in the average population.
The primary roadblocks to Dr. Hutter's treatment becoming routine are cost and risk. A bone marrow transplant is an extremely expensive procedure - the long hospital stay and transplantation procedure can end up costing over $200,000. But more importantly, it is extremely risky. The average patient who receives a bone marrow transplant – usually late stage cancer patients – has a 30% risk of death from getting the procedure alone. Such a mortality risk is not one that most physicians would allow for treatment from HIV when current antiretroviral regimens can allow patients to live for decades with HIV, almost as a chronic condition.
Dr. Margaret Fischl, director of the AIDS clinical research unit at the University of Miami Miller School of Medicine explains, “"That [Timothy Ray Brown] was young and got through [the bone marrow transplant] is quite remarkable. I would never give this to a healthy patient. I could never justify it. If you use this therapy, 30 percent of your patients could die from the intervention." She continues, "We tell our patients that this was a very particular situation. What made this work was that [Brown] got a very rare donor.”
Dr. Robert Gallo of the Institute of Human Virology at the University of Maryland, chimed in, more bluntly, ““It’s not practical and it can kill people.” Dr. Gallo is widely credited as being one of the co-discoverers of HIV in the early 1980's.
Still, the work of Dr. Hütter and his colleagues provides a reference point for other avenues of research, specifically in the oft maligned field of gene therapy. The idea is that the HIV patient's 'normal' immune system (one that doesn't have the CCR5-Delta 32 mutation) might be able to be genetically altered to start producing 'abnormal' CCR5 proteins that would prevent HIV from invading the CD4 T-cell.
Dr. Carl June and colleagues from the University of Pennsylvania have used a technique developed by Sangamo BioSciences (Richmond, CA) that forgoes the traditional gene therapy methods of using viruses to insert new DNA into a host cell, and instead uses naturally occuring proteins called “zinc fingers.” Each zinc finger protein can recognize a three-base sequence on DNA, and when multiple zinc fingers are put together, they can mimic naturally occuring proteins. More importantly, they can be used to cut DNA at specific sites, and when the DNA moves to repair itself, scientists can design zinc fingers to leave out the cut DNA during repair, or replace it with a different gene. Dr. June and Sangamo teamed up to start a clinical trial in mice, and used zinc fingers to disable the ability of the mices' T-cells to make the CCR5 HIV entry protein. When the treated T-cells were reintroduced into the HIV infected mice, they had a significant survival advantage over the untreated T-cells.
The case of Timothy Ray Brown is remarkable, and it has confirmed much research about the importance of T-cell surface proteins and how the HIV virus attacks and destroys the immune system. But for the average person unfortunately infected with HIV, it remains a special case, a treatment unavailable to them due to cost and risk. Dr. Fischl confirms, "We are having patients calling us and asking if they can stop their antiretroviral therapy -- and the answer is uncategorically no."