“Gene therapy offers hope of cure for HIV” The Independent has reported. The newspaper’s front page story said that a bone marrow transplant had eradicated the virus in a man who has lived with the condition for a decade.Brought to you by NHS Choices
This story was initially reported late last year, but has made headlines again following the publication of the medical case report. The research explains that the patient received two bone marrow transplants to treat his leukaemia from a person who carried two copies of a mutation that offers protection against HIV infection. Following the second transplant, the man did not use standard medication to control the virus, but unexpectedly he has no detectable viral levels 20 months later.
While this case will be of interest to people living with the condition, it is premature to claim that a cure for HIV has been found. The effect was seen in one patient, who already had a particular type of rare genetic mutation which can offer some resistance to the progress of HIV. Whether this success can be replicated in other individuals (with or without the genetic mutation) remains to be seen. However, the results are extremely important and will be of interest to the scientific and medical community, where more research will follow.Where did the story come from?
This research was conducted by Dr Gero Hutter and colleagues from the Department of Hematology, Oncology, and Transfusion Medicine and other academic and medical departments in Berlin. The work was funded by a grant from the German Research Foundation and published in the peer-reviewedNew England Journal of Medicine.
What kind of scientific study was this?
This was case report (a single person study) detailing the changes in the viral behaviour in a HIV positive man, after he received bone marrow transplants from a person with a specific genetic makeup.
During the process of HIV infection the virus uses certain receptors (proteins on the surface of cells) to gain entry to the T-cells (types of white blood cell that play an important role in immunity). One of these receptors is the CCR5 protein, which is produced using instructions contained in the CCR5 gene. A specific mutation of this gene responsible for the CCR5 protein is common among people of Northern European descent andconfers a level of protection against HIV.
For each gene in the human body there are two copies, called alleles, with one copy inherited from each parent. Inheriting two copies of the CCR5 mutation (one on each allele of the CCR5 gene), protects against HIV acquisition, while having one copy appears to slow disease progression.
In this study, researchers report on the case of a 40-year-old Caucasian man, who had been diagnosed with HIV infection more than a decade ago. This patient had been successfully treated using highly active antiretroviral therapy (HAART) for the previous four years. HAART is the standard combination drug treatment used in most HIV patients to suppress the action of the HIV virus.
The patient presented to doctors at hospital with newly diagnosed leukaemia (acute myeloid leukaemia) and was initially treated with chemotherapy to prepare for a bone marrow transplant. His HAART treatment was discontinued for a short time following complications, but then resumed. After three months of resumed treatment his HIV infection was no longer detectable.
After seven months the patient’s leukaemia relapsed, at which point he was given a bone marrow transplant from a donor. The donor was matched to the patient for a series of genes associated with the immune system. Matching these is a common practice in transplants, as it reduces the chances that the recipient’s body will reject the transplanted material.
The doctors had also genetically screened 62 possible donors, in order to choose bone marrow from a person carrying two copies of the mutated HIV protective CCR5 allele. The patient was also given drugs to assist with this grafting process, in which the recipient’s body accepts and uses the donor marrow.
The patient’s leukaemia relapsed 11 months after transplantation, and he was given further chemotherapy, irradiation and a second transplant from the same donor. The doctors then reported on his outcomes after these treatments, including an assessment of the level of HIV virus in the blood, up to 20 months after transplant.
What were the results of the study?
Following chemotherapy for acute myeloid leukaemia, the patient experienced some side effects, leading to complications including liver toxicity and kidney failure. His HAART treatment was stopped and there was, as expected, an increase in the amount of HIV virus in the blood.
After the patient’s leukaemia relapsed, doctors decided to treat him using a donor bone marrow transplant from a person who had two copies of the HIV protective CCR5 allele, to see if this would have an effect on high HIV as well as treat his leukaemia. During the screening process only one of the 62 potential donors had two copies of the HIV protective CCR5 allele. They used this person’s marrow for transplants into the HIV patient.
After the patient’s second relapse, his second set of treatments (more chemotherapy, radiation and a second transplant from the same donor) led to complete remission of the acute myeloid leukaemia, even after 20 months follow up.
Before transplantation the patient carried only one copy of the protective CCR5 mutation (he was heterozygous), but after the second transplantation, his white blood cells were shown to have two copies of the CCR5 mutation, as was present in the original marrow donor.
Prior to transplantation, there had been high levels of immune cells that respond to HIV infection (HIV-specific T-cells), but these fell to undetectable levels after transplantation. Other markers of immune response to HIV also dropped. The doctors also reported that serum levels of HIV genetic material (measured to determine how much virus is in the blood) remained undetectable during follow up.
A rectal biopsy found old types of immune cells (i.e. the ones that had only one copy of the CCR5 mutation), but there was no evidence of HIV virus in cells from the rectum.
What interpretations did the researchers draw from these results?
The researchers say that although discontinuation of antiretroviral therapy usually leads to a rapid rebound of HIV load within weeks, there was no active, replicating HIV detected 20 months after HAART treatment was stopped in this patient.
They say that this is ‘remarkable’ because having two copies of the CCR5 mutation is usually associated with ‘high, but not complete resistance’ to HIV. They say that long-lasting cells from the patient may be reservoirs for HIV, but that in this patient they found no evidence of HIV infection.
What does the NHS Knowledge Service make of this study?
This case study will be of interest to scientists and clinicians alike and will undoubtedly lead to more research. As the findings relate to only one case so far, the results cannot be generalised to all HIV patients, and it is too soon to conclude that a cure for the disease has been found.
The patient in question already carried one copy of the relatively rare CCR5 mutation, which according to the editorial, is linked with slower progression of the disease. How people with HIV who do not have the CCR5 mutation (the majority of people with HIV) will respond to such treatment is not yet known.
The researchers encourage more studies, saying that their report shows how important CCR5 receptors are during HIV infection and that their findings ‘should encourage further investigation’ into how these receptors can be targeted through treatments. Such studies will be eagerly awaited by the research, medical and patient communities. Though HAART is an effective treatment regimen for most people, the virus can develop resistance and the drugs can cause toxicities in some patients, so alternatives would be welcome.
An accompanying editorial to this research paper warns that evidence has shown that HIV can be lurking in cells in the lymph nodes and other parts of the body and that it may infect these tissues. The editorial reminds readers that bone marrow transplants require host cells to be destroyed or weakened through chemotherapy. This treatment can be very toxic and can lead to death.
The author, a doctor, says that an approach to target HIV without the need to eliminate host bone marrow would be helpful, e.g. by injection with a substance that could inactivate CCR5 receptors, preventing HIV from getting into immune cells.
Links to the headlinesGene therapy offers hope of cure for HIV.The Independent, February 12 2009
Links to the science
Hütter G, Nowak D, Mossner M et al.Long-Term Control of HIV by CCR5 Delta32/ Delta32 Stem-Cell Transplantation.NEJM 2009; Volume 360:692-698
Levy JA. Not an HIV Cure, but Encouraging New Directions.NEJM 2009; Volume 360:724-725