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HIV Cured in Berlin Patient -- What It Means
By Daniel J. DeNoon
Reviewed by Louise Chang, MD
Although the Berlin patient was treated in 2007, researchers are only now officially using the word "cure." That's because extensive tests -- including analyses of tissues from his brain, gut, and other organs -- detect no sign of lingering HIV.
Few people with HIV would want to go through the grueling and life-threatening cancer treatment that was part of this cure. And so far, the cure has not been duplicated in other HIV-positive leukemia patients who underwent similar treatment.
Yet the finding already has transformed AIDS research. What really happened? What does this mean for people who have HIV/AIDS? Here are WebMD's answers to these and other questions about the first HIV cure.
Why is HIV so hard to cure?
HIV infects a kind of white blood cell called a CD4 lymphocyte, a key player in the immune response. What makes HIV so sneaky is that it infects the very cells that are supposed to rub out viral infections.
HIV replicates in CD4 cells when they are activated -- that is, when they are triggered by an infection. But some HIV-infected cells become inactive before the virus replicates. They go into a resting mode -- and the HIV inside them becomes dormant until the cell is activated.
HIV drugs don't affect HIV hiding in resting cells. These cells represent a hidden reservoir of HIV. When treatment stops, the resting cells eventually become active. The HIV inside them replicates and quickly spreads. That's why current HIV treatments don't cure HIV.
How was the Berlin patient cured of HIV?
The Berlin patient was 40 years old when he developed leukemia. He had been infected with HIV for more than 10 years, but he was keeping his infection under control with a standard HIV drug regimen.
Standard treatment for leukemia is to kill off most of a patient's blood cells with chemotherapy -- a process called conditioning -- and then to rescue the patient with infusions of stem cells from a matched donor's blood or bone marrow. The new stem cells then repopulate the immune system and kill off the leukemia cells that survived the conditioning treatment.
The patient's doctor, Gero Hütter, MD, had an idea. Since HIV hides in white blood cells, why not try to cure the patient of leukemia and HIV at the same time? Instead of a normal donor, Huetter looked for a donor who carried the relatively rare mutation called CCR5delta32.
People with this mutation lack functional CCR5, the keyhole that HIV most often uses to enter cells. People who inherit two copies of this gene are highly resistant to HIV infection. So Hütter found a stem-cell donor who carried this mutation and used the cells to repopulate his patient's immune system.
During his recovery from the harsh conditioning treatment, the Berlin patient wasn't able to keep taking his HIV drugs. His HIV viral load shot up. But after receiving the HIV-resistant stem cells, his HIV dropped to undetectable levels -- and remained undetectable, even with extremely sensitive tests.
A year later, the patient's leukemia came back. He underwent a second round of chemotherapy and a second infusion of the HIV-resistant stem cells. It wasn't an easy treatment. The patient suffered intestinal and neurological symptoms, during which time biopsies were taken of various organs.
All of the tissues tested negative for HIV. "That was curious," says John Zaia, MD, chair and professor of virology at City of Hope, Duarte, Calif. Zaia has worked for more than a decade on developing stem-cell treatments for HIV and AIDS and has personally reviewed the Berlin patient's case with Hütter.
"There has been nobody who ever went off their anti-HIV medications without their HIV coming back," Zaia tells WebMD. "But this patient is still off treatment three and a half years later. Dr. Hütter is using the word 'cure' [in his new paper] for the first time. It is remarkable."
The Berlin patient's HIV remains totally undetectable. Moreover, his anti-HIV antibody levels continue to decline, which would not happen if there were still HIV present to stimulate antibody production. That's what led Hütter and colleagues to deem him cured.
Does the Berlin patient's treatment cure other people with HIV?
Not yet. The mutation that confers HIV resistance is relatively rare -- it's found in fewer than 2% of Americans and Western Europeans, in some 4% of Scandinavians, and is not present in Africans. A patient with leukemia can't wait very long for treatment, and it's not easy to find a matched donor who carries the double mutation.
"The Germans have tried and we have tried in the U.S., but we have not found another situation where we had an AIDS patient who could go forward for the transplant," Zaia says.
Why did the HIV cure work in the Berlin patient?
Nobody is really sure.
Three things happened during the Berlin patient's treatment.
First, chemotherapy killed off most of the cells infected with HIV. By itself, this would not be enough to cure HIV.
Second, the donor cells repopulated the patient's immune system. The new cells attacked and killed the patient's remaining white blood cells -- a process Zaia calls a "graft-versus-leukemia" response. This process likely killed off many of the remaining cells carrying HIV.
Third, the donor cells were resistant to HIV infection. As HIV emerged from resting cells, the virus helped kill off the old, susceptible cell. When the new donor cells expanded to take their place, the HIV had no place to go and withered away.
But none of these things fully explains what happened. One puzzle is that the stem cells used to repopulate the patient's immune system were HIV resistant -- but not HIV proof.
The cells lacked the most common doorway, CCR5, that HIV needs to infect cells. But people with long-term HIV infection usually carry HIV capable of using another doorway called CXCR4. And tests showed that the Berlin patient's blood carried HIV like this. Moreover, tests also showed that the donor cells were susceptible to infection via the CXCR4 pathway.
Even so, the Berlin patient mysteriously remains HIV free.
Does the Berlin patient's HIV cure mean other people can be cured of HIV?
Yes, but not right away. There's still no available cure for HIV. But the finding that it's really possible finally to cure AIDS has revitalized research.
"The Berlin case has moved the whole field," Zaia says. "Now major money is being directed from the National Institutes of Health into the area of a cure for HIV."
Several approaches show promise. Clearly it isn't practical -- or desirable -- to submit relatively healthy people with HIV to massive chemotherapy. But what if just a mild chemotherapy were used to create just enough room for HIV-resistant stem cells to gain a foothold?
Zaia's team is exploring the use of taking a patient's own cells and genetically engineering them to fight HIV. The first studies are being done on patients with HIV lymphoma, who already require chemotherapy. Four patients already have been treated with low doses of genetically modified cells -- and the good news is that the modified cells can survive and expand for at least two years.
Other researchers are using different techniques to alter stem cells to fight HIV. Until the Berlin patient, most experts considered all of these treatments unlikely to succeed. Now all eyes are upon them.
"In the future there will be a mild method of making space for these new HIV-resistant stem cells, so that they grow out and repopulate the immune system," Zaia says. "That is the goal. It may take a long time to get to that, but it will happen."
SOURCES: John A. Zaia, MD, professor and chair of virology and Aaron D. and Edith Miller chair of gene therapy, City of Hope, Duarte, Calif.Allers, K. Blood, published online Dec. 8, 2010.Hütter, G., New England Journal of Medicine, Feb. 12, 2009; vol 360: pp 692-698Hütter, G. Journal of the International AIDS Society, June 28, 2009; vol 12: p 10
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