amfAR researchers unable to find HIV in London transplant patient
Stem cell transplants are used to treat cancers of the immune system, and are typically used in people for whom other cancer treatments have failed. The stem cells are taken from adult donors or from cord blood, and when transplanted into the recipient, those stem cells mature into a new and healthy immune system.
Sometimes people living with HIV (PLWHIV) develop one of these immune cancers, and they become candidates for stem cell transplants. Under these circumstances, we have an opportunity to learn a lot about how HIV persists even when it’s well controlled by antiretroviral therapy (ART), and how replacing the immune system affects the ability of HIV to persist.
amfAR set up and provided funding to the IciStem consortium so that we could learn some important lessons about curing HIV that could be applied to designing a cure that would work in anyone, whether or not they receive a stem cell transplant. The researchers in IciStem analyze the blood and tissues of HIV-positive transplant recipients. They can then compare the outcomes between people who received transplants that have fully functional CCR5—the main doorway that allows HIV to enter cells— and those whose transplanted cells contained the CCR5-delta32 genetic mutation. This is of particular interest because cells with the genetic mutation are highly resistant to HIV.
Co-Principal Investigators Drs. Javier Martinez-Picado (front right) and Annemarie Wensing (center right), pictured with ICISTEM members including Dr. Gero Hütter, “the Berlin patient’s” physician, and Dr. Maria Salgado. Also pictured are Dr. Rowena Johnston (front, second from right) and Dr. Jeffrey Laurence (back row, right) of amfAR.
What/Who are IciStem, the London patient, and the Düsseldorf patient?
IciStem is a large consortium of HIV researchers and transplant specialists who are currently studying HIV in a cohort of 45 patients who have already received, or will soon receive, stem cell transplants to treat their cancers. Two of these patients – the London patient and the Düsseldorf patient – received cells from donors who had the CCR5-delta32 genetic mutation. Both have stopped taking ART without any signs of HIV returning, but it’s important to note that while the London patient has been off ART for 18 months, the Düsseldorf patient stopped taking ART only four months ago. PLWHIV who stop taking ART typically experience HIV rebound in 2-4 weeks, but the Mississippi child took 28 months to rebound, so although we’re hopeful that the London and Düsseldorf patients are cured, it will take more time to know for sure.
What kinds of things can we learn from these transplant patients?
When Timothy Ray Brown, the Berlin patient, was cured of both his cancer and his HIV following a transplant of CCR5-delta32 cells, the scientific community was unable to determine how crucial the mutation was to his cure outcome. Timothy also received a myeloablative conditioning regimen, as well as total body irradiation, designed to destroy the great majority of his own immune cells, before ultimately receiving two stem cell transplants. IciStem researchers will be able to determine the relative importance of the myeloablation, irradiation, the CCR5-delta32 genetic mutation, and number of transplants by comparing many HIV-positive stem cell transplant recipients in their cohort, because each patient receives a different combination of these factors.
If we learn that the CCR5-delta32 mutation is a critical factor, this finding points a promising way forward for gene therapy. In fact, other researchers have been working on CCR5 gene therapy in HIV for many years, and interesting results are emerging concerning how many of the transplanted cells need to have the genetic mutation in order to make a difference in the clinical outcome. You can learn more here about additional gene therapy strategies currently under investigation by amfAR researchers.
If specific subsets of immune cells are especially effective at clearing small numbers of remaining HIV cells, we can turn that knowledge into a more broadly applicable intervention.We also have the opportunity to learn from the processes by which a stem cell transplant may clear out any remaining vestiges of HIV. If the conditioning regimen before a transplant does not completely clear the HIV-infected cells, we can learn which cells of the newly transplanted immune system finish the job, and how. If specific subsets of immune cells are especially effective at clearing small numbers of remaining HIV cells, we can turn that knowledge into a more broadly applicable intervention.
By following transplant patients over time, and ultimately confirming they’re cured, we may be able to go back to samples collected earlier during the transplant and recovery process. Researchers could look at cells, proteins, and other substances in their blood to determine whether there are signs that could have predicted a cure, without having to wait years to know for sure. These biomarkers would then be valuable in assessing whether other more broadly applicable interventions have been effective in achieving a cure.
We can also compare the chemotherapy regimens the patients receive for their different cancers, and understand which regimens kill which subsets of cells. We may learn, for example, that some subsets of HIV-infected cells are the most important to target, and that others, even if they contain HIV, might be less important sources of rebounding virus and can be left alone.
And even transplant patients whose HIV we can still detect play an important role in our search for a cure. Because their remaining HIV reservoirs are so small, they may be ideal candidates to test early-generation immunotherapies for their ability to remove any remaining pockets of HIV.
Why do we need transplant patients to learn these things?
There are some things about curing HIV that you can only learn from people who have been cured. In the absence of other interventions so far that cure HIV, we need to learn those lessons from transplant patients.
For example, people living with HIV experience consequences of the persistence of the virus, such as damage to the architecture of their lymph nodes, that can hamper effective immune responses. If we remove the HIV, does their lymph node anatomy and function return to normal? If so, then we have learned that removing HIV may be sufficient for restoring lymph node health, without needing to devise additional interventions.
Similarly, PLWHIV have higher rates of atherosclerosis, a sign of possible heart disease and stroke. If those signs and symptoms return to normal after a stem cell transplant that removed HIV, then perhaps we’ve learned that no further interventions will be needed to deal with heart health after an HIV cure.
Dr. Johnston is an amfAR vice president and director of research.