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Sci Tech

Stem Cell Transplants Squashed HIV and Leukemia

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Stem-cell transplantations into a patient with acute myeloid leukemia and HIV have kept the leukemia in remission and the HIV undetectable for 20 months without the use of antiretroviral therapies.

The stem cells came from bone marrow in a human leukocyte antigen-compatible donor chosen because his cells lacked expression of chemokine receptor 5 (CCR5). Infection with HIV type 1 requires the presence of a CD4 receptor and either CCR5 or, less commonly, the CXC chemokine receptor (CXCR4).

The case report, published in the Feb.12 issue of the New England Journal of Medicine, demonstrates the importance of CCR5 in maintaining HIV infection. The findings should encourage development of new treatments targeting CCR5 that may reduce the need for other expensive and toxic antiretroviral therapies, wrote Dr. Gero Hütter of Charité Medical University of Berlin, and his associates (N. Engl. J. Med. 2009;360:692-8).

The findings don't necessarily mean that the transplant recipient was cured of HIV or that stem-cell transplants are the desired way to reduce CCR5 expression, but they raise some encouraging possibilities for therapeutic research, Dr. Jay A. Levy said in a commentary in the same issue (N. Engl. J. Med. 2009;360:724-5).

Although there has been no sign of HIV in the patient's blood for nearly 2 years, the virus may be lurking elsewhere in the patient's body and could reappear to cause disease in the lymph nodes, brain, gut, liver, kidneys, or heart, said Dr. Levy, professor of medicine in hematology and oncology at the University of California, San Francisco. A rectal biopsy 159 days after transplantation found CCR5-expressing macrophages in the patient's intestinal mucosa, but no evidence of HIV.

A type of HIV that binds to CXCR4 was present at low levels in the patient's blood and might emerge later, since this virus tends to grow in cells lacking CCR5 expression, he added.

Bone marrow transplants that involve ablation of the host's immune cells, as in this case, are risky and often fatal. Eliminating CCR5 from autologous stem cells and returning the cells to the host also carries a high risk. Research might focus instead on injecting a biochemical agent or genetic vector that would enter white blood cells and make them resistant to HIV by inactivating CCR5, Dr. Levy suggested.

"This case places further emphasis on gene therapies and treatments directed at blocking the CCR5 receptor with decoy drugs," he said.

Studies of so-called "long-term survivors" who have lived for decades with HIV without treatment and not developed AIDS or who have been exposed to HIV many times without becoming infected, have identified a genetic mutation - homozygous 32-bp deletion in the CCR5 allele - that results in lack of expression of the CCR5 gene and marked resistance to HIV infection. About 1%-3% of white Western males have this mutation.

In the current case, a 40-year-old white man with newly diagnosed acute myeloid leukemia had a 10-year history of HIV infection. He had been treated with highly active antiretroviral therapy (HAART) for 4 years and had been free of AIDS-related illnesses during that time. When he was diagnosed with leukemia, his serum HIV was undetectable.

He underwent two courses of induction chemotherapy and one course of consolidation chemotherapy for the leukemia, during which hepatic toxicity caused renal failure and led to discontinuation of HAART. An immediate rebound in his HIV viral load was contained by restarting HAART, and the virus was undetectable 3 months later.

When the leukemia relapsed after 7 months, the patient received allogeneic stem-cell transplantation with CD34-positive peripheral-blood stem cells from a donor who had been screened for homozygosity for the 32-bp deletion. He received a conditioning regimen, prophylaxis against graft-versus-host disease, and cyclosporine before the transplant and treatment with mycophenolate mofetil afterward. HAART was stopped the day before the procedure. Engraftment was achieved on day 13 after transplant.

A second relapse of leukemia 332 days after transplantation led to reinduction therapy with cytarabine and gemtuzumab, and on day 391, he received a second stem-cell transplant from the same donor after a single dose of whole-body irradiation.

The second transplant so far has resulted in complete remission of the leukemia and undetectable HIV 20 months after stopping HAART, Dr. Hütter reported.

"This observation is remarkable because homozygosity for CCR5 delta32 is associated with high but not complete resistance to HIV-1," he noted.

Dr. Hütter has been a consultant, adviser, or speaker for Celgene Corp. and Novartis Pharmaceuticals.

 

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