Hütter G, Nowak D, Mossner M, et al. N Engl J Med. 2009;360(7):692–698
PURPOSE OF THE STUDY. HIV infection of a target cell requires the expression of CD4 and a chemokine receptor. Early after HIV transmission, the chemokine coreceptor used most often is chemokine receptor 5 (CCR5). Approximately 1% of Northern European individuals possess homozygosity for a 32-base pair deletion (Δ32) in their CCR5 genes. These individuals are exceptionally resistant to HIV infection with CCR5-expressing HIV. The purpose of this study was to determine whether HIV could be suppressed by hematopoietic stem cell transplantation (HSCT) from a donor homozygous for CCR5 Δ32.
STUDY POPULATION. One HIV-infected adult was studied.
METHODS. The patient had been diagnosed with HIV ∼10 years before the development of acute myeloid leukemia. He had been treated effectively with antiretroviral agents and, at the time of the leukemia, his CD4+ T-cell count was 415 cells per mm3 and HIV RNA was undetectable. The leukemia was initially treated with chemotherapy but relapsed. The patient underwent allogeneic HSCT. The donor was chosen from a long list of potential donors who were HLA identical to the patient. The specific donor was chosen because of his homozygosity for the CCR5 Δ32 mutation.
RESULTS. Before HSCT, the patient's virus was shown to use the CCR5 coreceptor. The patient required 2 transplants because of acute myeloid leukemia relapse. However, the patient's antiretroviral therapy was stopped before the first transplant and was not restarted. After the second transplant, 100% chimerism of the patient's peripheral blood was demonstrated. Strikingly, the patient's viral load in plasma and lymphocytes remained undetectable for 20 months after HSCT and discontinuation of antiretroviral therapy.
CONCLUSIONS. This report provides “proof of concept” that HIV may be controlled (or eliminated) after HSCT with cells intrinsically resistant to HIV infection.
REVIEWER COMMENTS. The accompanying commentary (Levy JA. N Engl J Med. 2009;360:724–725), titled “Not an HIV Cure, But Encouraging New Directions,” perhaps understates what happened for this single patient; it is indeed possible that he was cured of his HIV. Although this is not applicable to the vast majority of HIV-infected individuals, this approach can be adapted for more-general use. For example, ongoing studies are being performed with autologous hematopoietic stem cells that have been genetically manipulated to mimic the unfavorable conditions for the virus that occur naturally in homozygous CCR5 Δ32 individuals. Insertion of genes that downregulate CCR5 expression, interfere with HIV replication, or both is an area of intense investigation. Although the initial costs of such an approach are substantial, the long-term costs of antiretroviral drugs and other interventions likely would make this approach, if it works, cost-effective.
- Copyright © 2009 by the American Academy of Pediatrics