A guest post from Nathalia Holt, Ph.D, an HIV researcher at the Ragon Institute at Massachusetts General Hospital. Her upcoming book, THE BERLIN PATIENTS, focuses on the personal stories of two men “whose HIV infections were cured in distinct yet essentially related ways.” Here, she tells talks to the Boston scientists whose recent findings suggest that — by maintaining antiretroviral therapy — it is possible to eradicate HIV with a standard bone marrow transplant.
In 2010, Dr. Tim Henrich, a fellow at Brigham and Women’s Hospital, was looking for a new area of research after a project fizzled out. He needed one that would span the precarious bridge that connects a fellowship to a faculty position.
“He was looking for something different to do,” Dr. Daniel Kuritzkes, director of AIDS research at Brigham & Women’s Hospital, said of his former fellow.
Henrich found his focus in the case of the Berlin patient, Timothy Ray Brown, who received a stem cell transplant from a donor naturally resistant to HIV and has been free of the virus ever since. By separating the components of the Berlin patient’s response, the pair concluded that –even without transplanting HIV resistant cells –it’s possible to eradicate HIV by maintaining antiretroviral therapy. Although preliminarily touted as a cure by some, these results actually teach us key lessons about the future of HIV eradication strategies.
As Kuritzkes puts it: “This is furthering the argument that antiretroviral therapy is fully suppressive.”
The story of the Berlin patient can be traced back to Boston, to a 2008 poster at the retrovirus conference Timothy, diagnosed with acute myeloid leukemia, received two bone marrow transplants from a donor who had a 32 base-pair deletion in the CCR5 gene, a mutation called Δ32. CCR5 is almost always required for HIV to enter immune cells. People who are homozygous for the Δ32 mutation have natural resistance to HIV. These mutant cells completely repopulated Timothy’s immune system, giving him resistance to clear the virus. Timothy, who had to go off antiretroviral therapy (ART) in 2007, has never gone back on medication. This is called a “functional cure,” Timothy may or may not have virus hidden in his body, as has been recently debated, but Timothy remains off therapy; cured.
Using the “c-word” when speaking of HIV treatment is something that researchers don’t take lightly, for fear of sparking false hope in patients. Despite this, Timothy’s experience has led to a new path for researchers, including one that led back to Boston.
The Brigham team looked at the separate components of the Berlin case. These included a conditioning regimen, a stem cell transplant, GVHD (graft versus host disease) and mutant, HIV resistant cells. How could each component be isolated to understand their individual effect on the virus? The researchers said they postulated that studying one component, the stem cell transplant, would allow them to characterize how the virus persists. What they found was quite different.
The team analyzed peripheral blood samples from two HIV+ patients at the Dana-Farber Cancer Institute who underwent hematopoietic stem cell transplants for treatment of lymphoma. Unlike the Berlin patient’s donor, the cells were not resistant to HIV. However, similar to Timothy’s experience, the donor cells homed to the patients’ bone marrow and then, over time, replaced the patients’ own immune cells. Unlike Timothy, the conditioning regimen the two patients received was minimal, meaning that they were able to continue on ART throughout the transplant.
The researcher said they were surprised to find that the latent virus (that pool of HIV unreachable by standard therapy) became undetectable following the transplant and has remained so for 2 and 3.5 years for each patient respectively. The investigators believe that by keeping the patients on ART, the donor cells were protected from HIV. These donor cells then repopulated the patients’ immune systems, effectively clearing the virus. This data was announced, to an excited audience, at the recent International AIDS Conference held in Washington, DC.
There are several reasons why this approach won’t work for most HIV+ individuals. First, receiving an allogeneic bone marrow transplant is not a trivial procedure. It carries significant morbidity and mortality risk; approximately 30% of patients receiving allogeneic transplants do not survive. As Henrich himself says, “If you don’t need a bone marrow transplant you shouldn’t get a bone marrow transplant.” Secondly, as neither of these patients has gone off therapy, we can’t be sure that the virus won’t rebound when the suppressive drugs are stopped. Lastly, while Timothy Brown has undergone lymph node, brain, and gut biopsies to measure hidden reservoirs of HIV, these two patients have not been similarly analyzed. We can’t yet know what burden of latent virus may be lurking in those tissues known to harbor HIV, or even how important these hidden reservoirs are.
This study is valuable because of what it tells us about the potential for eradicating the virus with antiretroviral therapy While not everyone can get a bone marrow transplant, this study provides direct evidence that latent virus can be eradicated. Kuritzskes and Henrich, who is now faculty, are evaluating two more HIV+ patients with the same therapy. In addition, they’re carefully considering interrupting ART for the two current patients in order to investigate the durability of their unique HIV-free outcome.
Whether it be through stem cell transplant, ZFN-mediated gene therapy, or novel agents, such as HDACi, capable of reactivating latent virus, it’s an encouraging time to be researching the virus, and, more importantly, to be living with HIV.