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Berlin Patient Still HIV-free 4 Years after Bone Marrow Transplant

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The "Berlin Patient" -- now known to be Timothy Ray Brown -- remains free of any detectable HIV in his blood, gut tissue, and other reservoir sites 4 years after receiving a bone marrow transplant containing stem cells from a donor with the CCR5-delta32 mutation, according to a report in the December 8, 2010 advance online edition of Blood. These findings, his doctors say, "strongly suggest that cure of HIV has been achieved in this patient.

This year has seen an increased emphasis on a cure for HIV, spurred in part by the proof-of-concept offered by the "Berlin Patient," an HIV positive man who needed a bone marrow transplant to treat leukemia.

HIV requires one of 2 co-receptors, CCR5 or CXCR4, to enter human cells. Individuals with a natural genetic mutation known as CCR5-delta32, who do not express CCR5 on their CD4 T-cells, are resistant to HIV infection. Those who do become infected may be "elite controllers" who maintain very low viral load without antiretroviral therapy (ART).

The Berlin Patient underwent leukemia treatment that involves using potent chemotherapy to kill off immune cells -- which eliminates the cancer -- and reconstituting the immune system with donated hematopoietic stem cells, which differentiate into all the different types of blood cells, including T-cells.

Gero Hütter and his team at Charite-University Medicine in Berlin searched the German bone marrow donor registry and managed to find a donor who was not only a compatible match, but also had a double or homozygous CCR5-delta32 mutation.

As reported in the February 12, 2009, New England Journal of Medicine, after the first transplant, researchers were unable to find any evidence of HIV, even though the patient stopped taking ART. He then received a second transplant from the same donor due to a relapse of leukemia. In the latest report, Hütter and colleagues provide an update on the patient's current status.

In every other known case to date, HIV remains in the body at low levels despite ART, hidden in resting memory T-cells and other viral reservoirs. When treatment is stopped, the virus begins replicating anew, leading to viral load rebound.

The Berlin Patient, however, shows no evidence of residual HIV and has not experienced disease progression. His immune system was successfully reconstituted, and now contains HIV-resistant CCR5-delta32 cells, like those of the donor. Furthermore, the researchers noted, "We found evidence for the replacement of long-lived host tissue cells with donor-derived cells indicating that the size of the viral reservoir has been reduced over time."

"[O]ur results demonstrate successful CD4+ T-cell reconstitution at the systemic level as well as in the largest immunologic organ [the gut] following CCR5-delta32/delta32 stem cell transplant, and additionally provide evidence for the reduction in the size of the potential HIV reservoir over time," they elaborated in their discussion.

CCR5-delta32 cells may not render a person completely resistant, since some strains of HIV may still be able to use the alternate CXCR4 co-receptor. The potent chemotherapy used in this case to ablate or kill off the man's original immune cells may have also played a role in the apparent eradication of HIV.

"Although the recovered CD4+ T-cells are susceptible to infection with [CXCR4] HIV infection, the patient remains without any evidence for HIV infection since more than 3.5 years after discontinuation of ART," the researchers concluded. "From these results, it is reasonable to conclude that cure of HIV infection has been achieved in this patient."

The Patient Comes Out

Concurrent with Hütter and colleagues' report in Blood, the Berlin Patient revealed his identity in a profile in the December 8 online issue of the German magazine Stern.

According to Google translation of the original article, Timothy Ray Brown, 44, is an American citizen living long-term in Germany. HIV positive since 1995, he developed leukemia in 2006. He was initially treated with chemotherapy, but without sustained response. Hütter -- who had little experience with HIV but had heard about the CCR-delta32 resistance mutation -- decided to try an unprecedented experiment. The case will go down in history as a milestone in the epidemic; not only does Brown show no signs of HIV, he also is in long-term remission from leukemia.

It is not possible, of course, to give every HIV positive person a stem cell transplant. In addition to the great expense, the ablation process can be fatal and there are too few CCR5-delta 32 donors to go around. But the Berlin Patient provides proof-of-concept needed to move forward with related approaches now under study, such as using zinc finger gene therapy to delete CCR5 from hematopoietic stem cells that are then returned to the body in the hope of creating an HIV-resistant immune system.

Investigator affiliations: Department of Gastroenterology, Infectious Diseases, and Rheumatology, Medical Clinic I, Campus Benjamin Franklin, Charite-University Medicine Berlin, Germany; Department of Hematology, Oncology, and Transfusion Medicine, Medical Clinic III, Campus Benjamin Franklin, Charite-University Medicine Berlin, Germany; Institute of Medical Virology, Helmut-Ruska-Haus, Campus Mitte, Charite-University Medicine Berlin, Germany; Institute of Pathology/Research Center ImmunoSciences (RCIS), Campus Benjamin Franklin, Charite-University Medicine Berlin, Germany.

12/14/10

Reference
K Allers, G Hütter, J Hofmann, and others. Evidence for the cure of HIV infection by CCR5delta32/delta32 stem cell transplantation. Blood (Abstract). December 8, 2010 (Epub ahead of print).

Other Source
The Berlin Patient: Der Mann, der HIV besiegte (The man who defeated HIV). Stern. December 8, 2010.