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CCR5-Delta-32 Stem Cell Transplants Unsuccessful in 6 Patients -- Berlin Patient Remains the Sole HIV Cure

Bone marrow transplants from donors with a naturally occurring mutation that protects immune cells from HIV failed to cure 6 additional HIV positive blood cancer patients, leaving "Berlin Patient" Timothy Ray Brown as the only person to show no signs of HIV infection several years after receiving this type of transplant, Brown's doctor Gero Hütter reported in the December 18 New England Journal of Medicine. Brown recently published his own story of being the only man known to be cured of HIV.

As previously reported, Timothy Brown underwent 2 bone marrow transplants to treat acute myeloid leukemia starting in 2007. He stopped taking antiretroviral therapy (ART) and underwent potent chemotherapy to kill off his existing cancerous immune cells. Stem cells in the donor bone marrow are then used to reconstitute the patient's immune system.

HIV requires either CCR5 or another co-receptor called CXCR4 to enter human cells. Individuals with a natural genetic mutation known as CCR5-delta-32 do not express CCR5 co-receptors on their CD4 T-cells, making them resistant to HIV infection. Hütter, then at Charite-University Hospital in Berlin, searched the German bone marrow donor registry and found an inidvidual who was both a compatible match for Brown and had a double or homozygous CCR5-delta-32 mutation.

As described in the February 12, 2009, New England Journal of Medicine, after Brown's first transplant researchers were unable to find evidence of HIV, even though he remained off ART. In the ensuing years Brown has undergone extensive evaluation by leading experts in the field -- including high-volume blood testing, leukapheresis, gut biopsies, and cerebrospinal fluid testing -- andstill shows no evidence of replication-competent HIV.

Researchers have puzzled over what factors might be responsible for Brown's sustained remission. A pair of HV positive bone marrow transplant patients in Boston who received a milder pre-transplant chemotherapy regimen appeared free of HIV for several months after undergoing experimental ART interruptions, but both eventually saw their HIV return.

In his recent NEJM letter to the editor, Hütter noted that 6 additional HIV positive leukemia or lymphoma patients have undergone stem cell transplants from CCR5-delta-32 homozygous donors. In addition to the Berlin Patient, 2 were treated elsewhere in Germany, 1 in the Netherlands, 1 in Spain, 1 in Chile, and I in Minneapolis in the U.S.

Unfortunately, none of these patients survived longer than a year due to cancer progression or complications of the transplant procedure. There were 3 deaths due to cancer relapse, 2 due to infections, and 1 due to graft-versus-host disease (GVHD), in which the newly reconstituted immune cells attack the patient's own body. Some experts believe GVHD may have played a role in Brown's cure.

In one case the patient experienced a rebound of HIV that used the CXCR4 co-receptor to enter cells, thus getting around the missing CCR5; this person died from a lymphoma relapse after 12 months. "So far it has remained unclear whether the co-receptor switch took place before allogeneic stem-cell transplantation or after transplantation in the absence of antiretroviral drugs," the doctors who treated this patient wrote. "Viral control might have been more effective if antiretroviral therapy had not been discontinued, but this remains speculative."

The other 5 patients survived for only a few months after their transplants so longer-term HIV outcomes could not be determined.

A Person Reflection

Timothy Brown described his experience as the only person cured of HIV in theDecember 17 advance edition of AIDS Research and Human Retroviruses, available free as part of a special issue on HIV cure research.

After a multi-year medical ordeal which included a relapse of leukemia, a second bone marrow transplant from the same donor, and complications that left him with brain impairment, Brown decided to come out publicly as the Berlin Patient. In 2012 Brown and the World AIDS Institute founded the Timothy Ray Brown Foundation focusing on HIV cure research.

"I did not want to be the only person in the world cured of HIV; I wanted other HIV+ patients to join my club," Brown wrote. "I want to dedicate my life to supporting research to search for a cure or cures for HIV!"

1/12/15

References

G Hütter. More on Shift of HIV Tropism in Stem-Cell Transplantation with CCR5 Delta32/Delta32 Mutation (letter to the editor). New England Journal of Medicine 371(5):2437-2438. December 18, 2014.

J Verheyen, S Esser, and L Kordelas. Authors' reply. New England Journal of Medicine 371(5):2438. December 18, 2014.

TR Brown. I Am the Berlin Patient: A Personal Reflection. AIDS Research and Human Retroviruses. December 17, 2014 (Epub ahead of print).