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Stem-Cell Transplantation Enables Long-Term HIV Control

A leukemia patient lost his CCR5 receptors and achieved remission of both leukemia and HIV infection.

Good drugs are available for keeping HIV at bay, but the many downsides of lifelong drug treatment (e.g., cost, side effects, access) fuel the continued search for a cure. A case report from Germany now suggests that manipulation of the CCR5 receptor is the key to long-term, drug-free virologic control.

A 40-year-old white man with longstanding HIV infection (>10 years) received a diagnosis of acute myeloid leukemia (AML). At the time, he was receiving an efavirenz-based regimen and had a CD4 count >400 cells/mm³ and an undetectable viral load. He underwent two courses of induction chemotherapy and one course of consolidation therapy, but the AML relapsed. He then underwent allogeneic stem-cell transplantation with a human leukocyte antigen–matched donor who had been screened specifically for homozygosity of the CCR5 32 allele. Remission from AML was achieved, but relapse occurred almost a year later, prompting a second transplant from the same donor. Complete AML remission was realized and maintained throughout reported follow-up (20 months from the first transplantation).

Meanwhile, virologic control of HIV was lost during the initial chemotherapy — when drug toxicity mandated discontinuation of antiretrovirals — and was then regained when antiretrovirals were resumed. The day before the first transplantation, all antiretrovirals were stopped permanently. Nonetheless, HIV viral load remains undetectable in the patient’s blood and bone marrow at 23 months (per author correspondence), and CD4-cell counts have returned to premorbid levels.

With engraftment, PCR assays confirmed complete chimerism, with a shift from a pretransplant heterozygous genotype for CCR5 to a homozygous 32/32 genotype. A rectal biopsy performed between transplants showed persistence of CCR5-expressing macrophages in the rectal mucosa, but HIV DNA was not detected therein. Ultradeep sequencing analysis before transplantation indicated that 2.9% of the patient’s viral population was CRCX4-using or dual-tropic, but these variants never emerged during follow-up.

Comment: Bone marrow transplantation has periodically been advocated as a path to HIV cure, but past efforts have been uniformly unsuccessful. An editorialist points out that dubbing this latest effort a complete success is still premature: With time, the patient’s CXCR4-using HIV might reemerge, or his remaining CCR5-expressing cells might lose whatever is protecting them. However, the case does suggest that targeting CCR5 by other methods — molecular inactivators or RNA fragments that downregulate expression — might be a powerful strategy for delaying onset of disease, if not actually achieving cure.

— Abigail Zuger, MD

Published in AIDS Clinical Care February 13, 2009

Citation(s):

Hütter G et al. Long-term control of HIV by CCR5 delta32/delta32 stem-cell transplantation. N Engl J Med 2009 Feb 12; 360:692.

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Levy JA. Not an HIV cure, but encouraging new directions. N Engl J Med 2009 Feb 12; 360:724.

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• Medline abstract (Free)