- Category: Search for a Cure
- Published on Tuesday, 31 July 2012 00:00
- Written by Liz Highleyman
Two men who underwent bone marrow transplants for lymphoma using milder chemotherapy that allowed them to remain on antiretroviral therapy (ART) show no traces of HIV, researchers reportedlast week at the XIX International AIDS Conference (AIDS 2012) in Washington, DC. While not repeating the "Berlin Patient" HIV cure, these cases offer further insight into possible strategies for eradicating the virus.
Timothy Brown -- better know as the "Berlin Patient" -- is the first person known to have been cured of HIV after receiving 2 bone marrow transplants to treat leukemia from a donor with an uncommon genetic mutation, CCR5-delta-32, that causes absence of CCR5 co-receptors, one of the gateways HIV uses to enter cells.
Brown stopped taking ART before his first transplant, and 5 years later he still does not have detectable replicable virus in his blood, immune cells, gut, or other tested tissues. While there has been some debate about whether Brown has any remaining bits of HIV in his body, it is clear that he has achieved a functional cure, or viral control without treatment. This "proof-of-concept" has been credited with reviving the HIV cure research field.
Prior to transplantation, Brown underwent intensive chemotherapy and radiation that killed off his own immune cells to get rid of the leukemia, and his immune system was reconstituted by the CCR5-free stem cells in the donated bone marrow.
This procedure is high-risk and would not be done on someone without a life-threatening illness, however, so researchers have been waiting for further "natural experiments" to learn more about how Brown's treatment might have cured his HIV.
Daniel Kuritzkes and Timothy Henrich from Brigham and Women's Hospital in Boston described 2 HIV positive men who underwent allogeneic stem cell transplants to treat lymphoma. One was infected with HIV perinatally, the other through sexual contact, and they had been on ART for 3-4 years at the time of transplantation.
Both patients were CCR5-delta-32 heterozygous, meaning they carried a single copy of the mutation (not 2 copies, like Brown's donor) so their cells were only partially resistant to HIV; the donors also did not have naturally resistant cells. The men had HIV RNA suppressed on ART before their transplants, but still had residual HIV DNA in CD4 T-cells and possibly other reservoirs.
They men both received less toxic "reduced intensity conditioning" chemotherapy and did not get whole-body radiation, unlike Brown, which enabled them to remain on antiretroviral drugs.
At an HIV cure press conference sponsored by the International AIDS Society, Kuritzkes explained that over time the transplanted donor cells replaced the recipients' own lymphocytes. One patient has now been followed for 2 years and the other for 3.5 years, and both have "no traces of virus" in their plasma or purified T-cells, he said.
Henrich provided further details during an oral abstract session. The researchers analyzed stored samples collected before and after bone marrow transplantation. They quantified HIV-1 DNA from peripheral blood mononuclear cells (PBMCs), counted 2-LTR circles from PBMC episomal DNA (an indicator of replicating HIV that is unable to integrate itself into host cell chromosomes), and measured plasma viremia using a single-copy assay.
HIV DNA was detectable prior to and during the first 2-3 months after the transplants, but it was no longer evident 8-17 months post-transplantation. 2-LTR circles were not detected at any time point. The two men also showed decreases in HIV-specific antibodies, suggesting there is not enough remaining virus to trigger an immune response.
Both patients experienced graft-vs-host disease, in which transplanted immune cells attack the recipient's body, which was treated with immunosuppressive therapy (prednisone or tacrolimus/sirolimus). It is not yet clear whether this contributed to loss or control of HIV.
Since the donor stem cells i did not lack CCR5 co-receptors, Kuritzkes speculated that replacing all the patients' original immune cells apparently got rid of a reservoir of latent HIV, while continuing ART protected the newly introduced cells from infection. "It's a form of PrEP [pre-exposure prophylaxis] on the cellular level," he said.
Kuritzkes and Henrich were careful not to refer to these patients as cured. They remain on antiretroviral drugs, and it is not yet known whether their viral load would rebound if they were to stop treatment, which is a risky proposition. While the patients have been advised to stay on ART for the time being, Kuritzkes concluded, "We have shown that inherently susceptible cells can be protected."
T Henrich, G Sciaranghella, JZ Lee, DR Kuritzkes, et al. Long-term reduction in peripheral blood HIV-1 reservoirs following reduced-intensity conditioning allogeneic stem cell transplantation in two HIV-positive individuals. XIX International AIDS Conference. Washington, DC, July 22-27, 2012. Abstract THAA0101.
International AIDS Society. New HIV Cure Research Released Today at the XIX International AIDS Conference (AIDS 2012). Press release. July 26, 2012.