Doctors Claim Stem Cell Cure
posted: 14/12/2010
Doctors who transplanted stem cells with HIV resistance to an HIV-infected man with leukaemia in 2007 say they believe he has been cured of HIV. The man is very unusual and treating most people in the same way won't work. But it does suggest new things to study.
A very small proportion of people (under 1 in 100) have natural resistance to HIV. This man was given matching bone marrow from a donor who has natural resistance to HIV infection. The donor doesn’t have the CCR5 co-receptor that HIV uses to lock onto the CD4 cell. People with this genetric mutation are almost completely protected against HIV infection.
The case was first reported at the 2008 Conference on Retroviruses and Opportunistic Infections in Boston, and Berlin doctors subsequently published a detailed case history in the New England Journal of Medicine in February 2009.
‘Reasonable to conclude’ HIV was cured
They have now published a follow-up report in the journal Blood, arguing that based on the results of extensive tests, “It is reasonable to conclude that cure of HIV infection has been achieved in this patient.”
The man's treatment story
The 'Berlin patient' is an HIV-positive man who developed acute myeloid leukaemia, received successful treatment and subsequently experienced a relapse in 2007 that required a transplant of stem cells.
Doctors chose stem cells from someone who has a very unusual genetic profile: a mutation inherited from both parents that resulted in CD4 cells without the CCR5 receptor. This mutation, called CCR5 delta 32 homozygosity, is present in less than 1% of Caucasians in northern and western Europe, and is associated with a reduced risk of becoming infected with HIV.
All new infecting viruses need to use the CCR5 receptor on CD4 cells when infecting an immune system. Later on in HIV infections the CXCR4 receptor can also be used by HIV as a route into the CD4 cell.
Complex, costly, lengthy treatment
Before the stem cell transplant the man received chemotherapy treatment to destroy most of his immune cells and total body irradiation, and was given immunosuppressive drugs to prevent rejection of the transplanted stem cells.
Antiretroviral therapy was halted on the day of the transplant, and the man had a second stem cell transplant 13 days after the first one, because his leukaemia got worse.
The man continued to have immunosuppressive treatment to prevent rejection for 38 months, and at 5, 24 and 29 months post-transplant colon biopsies were taken to investigate possible graft-versus-host disease in the intestine. At each investigation additional samples were taken to check for signs of HIV infection in the abundant immune cells of the gut wall.
During the 38 month follow-up period the donor CD4 cells repopulated the mucosal immune system of the gut, to such an extent that the frequency of CD4 cells was almost twice as high as in HIV-negative healthy controls, and this phenomenon was also seen in a control group of ten HIV-negative individuals who received stem cell transfers.
The repopulation of CD4 cells was accompanied by the complete disappearance of host CD4 cells, and after two years the patient had the CD4 count of a healthy adult of the same age.
Longer lived HIV cells disappear
One of the challenges for any approach to curing HIV infection is long-lived immune system cells, which need to be cleared before a patient can be cured. In the case of the Berlin patient CCR5-bearing macrophages could not be detected after 38 months, suggesting that chemotherapy had destroyed these longer-lived cells, and that they had also been replaced by donor cells.
The German researchers and San Francisco-based immunologist Professor Jay Levy believe that the findings point to the importance of suppressing the production of CCR5-bearing cells, either through transplants, or gene therapy.
The man did not restart anti-HIV treatment after the transplant.
Ultimate undetectable
Nevertheless HIV remained undetectable by both viral load testing (RNA) and tests for viral DNA within cells, and HIV antibody levels declined to the point that the patient has no antibody reactivity to HIV core antibodies, and only very low levels of antibodies to the HIV envelope proteins.
Seventeen months after the transplant the patient developed a neurological condition, which required a brain biopsy and lumbar puncture to sample the cerebrospinal fluid for diagnostic purposes. HIV was also undetectable in the brain and the CSF.
An additional indication that HIV is not present lies in the fact that the patient’s CD4 cells are vulnerable to infection with virus that targets the CXCR4 receptor. If any virus with this preference was still present, the researchers argue, it would be able to swiftly infect the large population of memory CD4 cells that has emerged.
The Berlin patient speaks to the press
The `Berlin patient`, Timothy Ray Brown, a US citizen who lives in Berlin, was interviewed this week by German news magazine Stern.
His treatment for leukaemia was gruelling and lengthy. Brown suffered two relapses and underwent two stem cell transplants, as well as a serious neurological disorder that flared up when he seemed to be on the road to recovery.
The neurological problem led to temporary blindness and memory problems. Brown is still undergoing physiotherapy to help restore his coordination and gait, as well as speech therapy.
Friends have noticed a personality change too: he is much more blunt, possibly related to the neurological problems.
On being asked if it would have been better to live with HIV than to have beaten it this gruelling and complex way he says “Perhaps. Perhaps it would have been better, but I don’t ask those sorts of questions anymore.”
Stern also interviewed Dr Gero Hütter, who was in charge of Timothy Brown’s treatment. Dr Hütter told Stern that as a scientist he was “in the right place, at the right time” and that “for me it is important to have overthrown the dogma that HIV can never be cured. Something like this is the greatest thing one can achieve in medical research”.
Implications for HIV treatment future
If a cure has been achieved, it suggests one way to a cure for HIV infection is through genetically engineered stem cells.
The German researchers and San Francisco-based immunologist Professor Jay Levy believe that the findings point to the importance of suppressing the production of CCR5-bearing cells, either through transplants, or gene therapy.
Finding donors or transforming stem cells
Scientists were sufficiently intrigued by the Berlin patient that they met in Berlin in 2009 to discuss how they could coordinate efforts to identify CCR5-delta32 homozygous donors and expand the supply of stem cells from these donors, for example through sampling blood cells from the umbilical cord of babies born to mothers who are homozygous for CCR5-delta32, in order to eventually facilitate stem-cell therapy.
Gene therapy techniques which transform stem cells – and all their descendents – into cells resistant to HIV entry may be more practical than looking for rare matching donors.
Several US research groups announced in October 2009 that they had received funding to explore techniques for engineering and introducing CCR5-deficient stem cells.
If these approaches prove successful they will be expensive, so in the early stages it is likely that they would be reserved for people with no remaining treatment options or a cancer requiring bone marrow or stem cell transfer.
As Timothy Brown’s experience shows, curing HIV infection through ablative chemotherapy, immunosuppressive drugs and stem cell transfer is not a course of treatment for the faint-hearted. It has required courage, determination and a lot of support to become the first person to be pronounced `cured` of HIV infection.
Source with references
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