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HIV remained undetectable after hematopoietic stem cell transplant

Up to 4.3 years after transplant, HIV DNA was not detected in the blood and rectal tissue among two patients with HIV who underwent hematopoietic stem cell transplantation for cancer, researchers reported at the 2013 International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention in Kuala Lumpur, Malaysia.

Researchers from Brigham and Women’s Hospital, Harvard Medical School and Massachusetts General Hospital in Boston conducted the study. The two patients had received reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation from wild-type CCR5 donors. The researchers collected peripheral blood mononuclear cells by leukapheresis from both patients and rectal tissue from one patient to quantify HIV DNA and perform viral co-culture from CD4+ T lymphocytes.

No HIV DNA was detected in any of the peripheral blood mononuclear cells from either patient, suggesting that the peripheral viral reservoir size decreased by 3 log10 to 4 log10. They also found no HIV p24 antigen in the CD4+ T cells, and there also was no HIV DNA detected in the rectal tissue.

For more information:

Henrich T. Abstract WELBA05. Presented at: 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention; June 30-July 03, 2013; Kuala Lumpur, Malaysia.

Up to 4.3 years after transplant, HIV DNA was not detected in the blood and rectal tissue among two patients with HIV who underwent hematopoietic stem cell transplantation for cancer, researchers reported at the 2013 International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention in Kuala Lumpur, Malaysia.

Researchers from Brigham and Women’s Hospital, Harvard Medical School and Massachusetts General Hospital in Boston conducted the study. The two patients had received reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation from wild-type CCR5 donors. The researchers collected peripheral blood mononuclear cells by leukapheresis from both patients and rectal tissue from one patient to quantify HIV DNA and perform viral co-culture from CD4+ T lymphocytes.

No HIV DNA was detected in any of the peripheral blood mononuclear cells from either patient, suggesting that the peripheral viral reservoir size decreased by 3 log10 to 4 log10. They also found no HIV p24 antigen in the CD4+ T cells, and there also was no HIV DNA detected in the rectal tissue.

For more information:

Henrich T. Abstract WELBA05. Presented at: 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention; June 30-July 03, 2013; Kuala Lumpur, Malaysia.

    Perspective
    David Cohn

    David Cohn

    These two patients differ from the Berlin patient in that: 1) they did not receive whole-body irradiation and ablative chemotherapy (that gets rid of any remaining host cells that may be infected with HIV); and 2) the donor cells did not have the delta 32 mutation that results in CD4 receptors that are CCR5 negative in new cells (conferring resistance to re-infection by HIV).

    It is interesting the investigators hypothesize that following the allogeneic bone marrow transplants that graft vs host disease (ie, donor cells killing host cells), in combination with ongoing ART, led to the potential eradication of HIV in these two patients. However, they have been off ART for only 8 and 15 weeks, so further follow-up is needed to determine if they are truly “cured” of HIV, or perhaps more properly stated, “in remission.”

    The study is of little practical value for almost all patients with HIV/AIDS, but does inform the field on attempts at HIV eradication from viral reservoirs, a very hot area of current HIV research.

    • David Cohn, MD
    • Infectious Disease News Editorial Board member

    Disclosures: Cohn reports no relevant financial disclosures.

    Perspective
    Christine Durand

    Christine Durand

    These results are very exciting. Many of us in the field believe that the only true test of cure is interrupting patients’ ART. One of the patients has been off of therapy for 15 weeks and the other patient has been off for 7 weeks. The fact that HIV has not yet rebounded with this interruption of therapy is promising. If these patients are cured, they would be the third and fourth patients reported to be cured, but the mechanism of cure in each case is different. The Berlin patient, who was the first reported case of cure, received a form of gene therapy by receiving a bone marrow transplant from a donor with a favorable genetic mutation. In the case of the baby reported at this year’s CROI, it is likely that early ART prevented the establishment of a latent long-lived infection. In the Boston patients reported here, cure may have been achieved due to replacement of the hematopoietic system with transplanted donor cells that were protected not by a genetic mutation, but by ART. Practically, this particular report will change the way bone marrow transplants in HIV patients with blood cancer are performed, in that continuing ART will be a priority during transplant. Previously, ART was often interrupted during transplant because of drug interactions and other challenges, but if ART during transplant can lead to HIV cure, then we will find strategies to overcome the challenges of continuing ART. In terms of the larger HIV-infected population, however, cure is a long way off. But these cases do teach us about important aspects of the biology of HIV latency that will inform continued cure research.

    • Christine Durand, MD
    • Assistant professor, Johns Hopkins University School of Medicine

    Disclosures: Durand reports no relevant financial disclosures.

    Perspective

    The patients described in this abstract were on antiretrovirals at the time of the reduced-intensity conditioning allogeneic hematopoetic stem cell transplantation 4.3 years ago and remained on their ART until 15 and 8 weeks ago, respectively, at time of presentation at IAS 2013. The researchers looked diligently for HIV-1 DNA or replication competent proviruses in peripheral blood mononuclear cells and rectal tissue. None was found. 

    These findings are complex but offer great insight into the future of HIV research in this area. Stem cell transplantation is not a viable option for all HIV-positive patients due to the high morbidity and mortality rates associated with this treatment. However, this research shows that is possible to eradicate the HIV reservoir. This notion was previously unclear. These findings build upon the results of Timothy Ray Brown, also known as “The Berlin Patient,” Mr. Brown needed a stem cell transplant to treat his acute myeloid leukemia. He was given stem cells from a donor, who was a CCR5 delta 32 homozygote. The donor was intentionally chosen with the hope that Mr. Brown’s new T cells would be resistant to HIV infection. It has been more than 5 years since Mr. Brown’s transplant and he remains free of HIV replication. CCR5 is a co-receptor used by most strains of HIV, along with CD4, to enter T cells. Physicians and scientists thought the reason that HIV did not “come back” was that Mr. Brown’s new T-cells (those derived from donor stem cells) were resistant to infection with HIV. 

    The patients presented by Drs. Henrich and Kuritzkes received cells from wild-type CCR5 donors. Their new T-cells are not resistant to HIV infection. The patients were conditioned with chemo and radiation therapy. This conditioning destroys the native bone marrow and lymphocytes. After conditioning, each patient was given stem cells from a “normal” donor and each was maintained on their HIV medications. After a period of years in which no evidence of HIV infection could be found, the HIV medications were stopped. Months later, there is no sign of HIV replication in either patient. These data suggest that the reservoir or “pool” of latently infected cells can be destroyed completely. In Mr. Brown’s scenario, it was assumed that the “pool” was not and could not be destroyed and that the new T cells, resistant to HIV infection, were essential to his “cure.” These new data contradict that theory and support the hypothesis that the “pool” can be eliminated and a “cure” can be mediated through this process alone.

    These findings give hope to the prospects for cure of all HIV patients. One can imagine a future therapy, much more benign than the conditioning associated with stem cell transplantation, that could eliminate the “pool” and “cure” the patient. Perhaps a form of mild autologous stem cell transplantation might be designed, which has minimal side effects. Currently, it is difficult to envision how any therapy, which involves the elimination of a patient’s existing T cells, could be as benign as today’s HIV medication regimens. 

    • Erin Murphy Santos, PA-C, MPH, and Stephen M. Smith, MD
    • Smith Center for Infectious Diseases and Urban Health East Orange, Newark

    Disclosures: Santos and Smith report no relevant financial disclosures.

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