Seven teams of leading scientists to share close to $2.4 million for collaborative efforts to pursue HIV/AIDS eradication
It has been six years since the first case of a cure was reported in an HIV-positive man with leukemia who received a stem cell transplant from a donor with a rare genetic mutation conferring resistance to HIV infection. The case of “the Berlin patient” raised as many questions as it answered, and it dramatically changed the trajectory of HIV/AIDS research. Among the recipients in the latest round of cure-focused research grants from amfAR, leading researchers from all over the world will continue to investigate precisely how the Berlin patient was cured and will explore other potential cure strategies that could one day be applied to the millions of people living with HIV/AIDS.
The new grants, totaling nearly $2.4 million, will support the work of seven teams of scientists working within the amfAR Research Consortium on HIV Eradication (ARCHE), an initiative launched in 2010 to explore potential strategies for eliminating HIV infection. This brings amfAR’s investment in cure-focused research to more than $6 million so far this year.
“The case of the Berlin patient was a seminal development in HIV/AIDS research and caused many in the scientific community to think, for the first time, that a cure for HIV was actually possible,” said amfAR CEO Kevin Robert Frost. “It certainly reinforced amfAR’s commitment to finding a cure, and our ARCHE program is a reflection of our unwavering quest to bring this epidemic to an end in our lifetime.”
Many researchers around the world have tried, so far unsuccessfully, to duplicate the case of Timothy Brown (the Berlin patient) to determine which were the crucial components of a highly complex intervention— chemotherapy, total body irradiation, genetic mutation present in the transplanted cells, and/or the graft-versus-host disease that ensued. The largest award in this round of grants will support a consortium of European researchers—including Gero Hütter, M.D., the oncologist credited with Brown’s cure—to study the outcomes of HIV patients who undergo different types of stem cell transplants. The European researchers, led by Javier Martinez-Picado, Ph.D., of IrsiCaixa in Spain and Annemarie Wensing, M.D., Ph.D., of University Medical Center Utrecht in the Netherlands, anticipate having several HIV patients in need of stem cell transplants and they hope to generate new knowledge that can inform more widely applicable interventions.
Meanwhile, another team of European researchers led by Vanderson Rocha, M.D., Ph.D., of National Health Service Blood and Transplant, Cord Blood Banks, Oxford, in the United Kingdom will pre-screen a pool of blood stem cell donors for CCR5-delta32, the genetic mutation that renders people highly resistant to HIV infection and is believed to be responsible, at least in part, for Timothy Brown’s cure. Naturally present in around one to two percent of Caucasians, the mutation is most prevalent in Northern Europe and the researchers will focus their attention initially on cord blood banks in Sweden and Finland. They hope to determine which donors, based on their tissue types, have the greatest potential to harbor the CCR5 genetic mutation.
A team of researchers in the U.S. will receive funding to address one of the most pressing challenges in HIV research: determining whether people whose HIV has dropped to an undetectable level have been cured, or whether current tests are simply not sensitive enough to detect every last remnant of virus. In a recent amfAR-funded study, Timothy Henrich, M.D., of Brigham and Women’s Hospital in Boston described two patients who had received stem cell transplants to treat their cancer and in whom HIV could no longer be detected using the most sophisticated tests currently available. When the patients stopped taking antiretroviral therapy, their virus eventually returned, indicating that they had not been cured. Dr. Henrich will collaborate with Ramesh Akkina, Ph.D., of Colorado State University in an effort to infuse cells taken from the Boston patients prior to viral rebound into mice engineered to contain human immune systems. If the mice become infected, this would represent a more sensitive test of HIV persistence than any other test currently available.
“amfAR’s ARCHE program is continuing its tradition of pinpointing the important outstanding questions in research and targeting funding to those researchers who can answer them, wherever they are in the world,” said Dr. Rowena Johnston, amfAR’s vice president and director of research. “We are tremendously excited by the findings these grants could yield and confident they will open a number of new pathways to a cure.”
ARCHE-funded research teams and their projects are as follows:
Ramesh Akkina, Ph.D. – principal investigator
Colorado State University, Fort Collins, CO
Timothy Henrich, M.D. (Brigham and Women’s Hospital) – collaborating investigator
$250,837
Unmasking the latent HIV reservoir using humanized mice: One of the most pressing current challenges in HIV research is determining whether those in whom HIV levels have dropped so low they cannot be detected have been cured, or whether current tests are simply not sufficiently powerful to detect remaining virus. In a recent amfAR-funded study, Dr. Henrich described two HIV patients (known as the “Boston patients”) who had received stem cell transplants to treat their cancer and in whom HIV could no longer be detected using the most sophisticated tests currently available. When the patients stopped taking antiretroviral therapy, their virus eventually returned after several months, indicating that they had not been cured. Drs. Akkina and Henrich propose to infuse cells taken from the Boston patients prior to viral rebound into mice engineered to contain human immune systems. If the mice become infected, this would represent a more sensitive test of HIV persistence than any other test currently available.
Nicolas Chomont, Ph.D. – principal investigator
Vaccine and Gene Therapy Institute – Florida, Port St Lucie, FL
Jintanat Ananworanich, M.D., Ph.D. (The Henry M. Jackson Foundation for the
Advancement of Military Medicine, Inc.) – collaborating investigator
Asier Saez-Cirion, Ph.D. (Institut Pasteur) – collaborating investigator
Sarah Palmer, Ph.D. (University of Sydney) – collaborating investigator
Steven Deeks, M.D. (UCSF) – collaborating investigator
Mathias Lichterfeld, M.D., Ph.D. (Massachusetts General Hospital) – collaborating investigator
Nittaya Phanuphak, M.D., Ph.D. (Thai Red Cross AIDS Research Center) – collaborating investigator
$584,118
Identifying and targeting persistence in T cell subsets during ART: During their first year of funding, Dr. Chomont and his colleagues discovered that HIV tends to persist to different extents and in different forms depending on the T cell subset. They plan to continue their work during this second year of funding by characterizing the mechanisms that may operate within different T cell subsets that permit the establishment and persistence of HIV reservoirs. Their studies will culminate in a determination of whether different types of T cells harbor HIV in ways that will be differentially difficult to clear. New members in their group will allow the characterization of several very interesting patient cohorts that will inform efforts on curing HIV.
Scott Kitchen, Ph.D. – principal investigator
University of California Los Angeles, Los Angeles, CA
Jerome Zack, Ph.D. (UCLA) – collaborating investigator
Irvin Chen, Ph.D. (UCLA) – collaborating investigator
Hans-Peter Kiem, M.D. (University of Washington) – collaborating investigator
$300,000
Programming stem cells with a chimeric antigen receptor to eradicate HIV: One reason HIV infection cannot be cleared by the immune system is that the infection itself kills off many immune cells and leaves other immune cells dysfunctional. Dr. Kitchen and colleagues spent the first year of their ARCHE funding genetically engineering stem cells that would potentially be self-renewing and impervious to the effects of the virus. For this second year of funding, they plan to transplant the cells into monkeys that have been infected with a closely related virus called SHIV, a fusion between HIV and SIV, a virus that naturally infects monkeys. They will measure the extent to which these transplanted immune cells will be able to reduce or perhaps even eliminate the virus from the infected monkeys. If successful, these findings could serve as the basis for gene therapy approaches that could be used more widely in infected people.
Javier Martinez-Picado, Ph.D. – principal investigator
IrsiCaixa, Badalona, Spain
Annemarie Wensing, M.D., Ph.D. – principal investigator
University Medical Center Utrecht, Utrecht, Netherlands
Monique Nijhuis, Ph.D. (University Medical Center Utrecht) – collaborating investigator
Jan van Lunzen, M.D., Ph.D. (University Medical Center Hamburg) – collaborating investigator
Rafael Duarte, M.D., Ph.D. (Catalan Institute of Oncology) – collaborating investigator
Jurgen Kuball, M.D., Ph.D. (University Medical Center Utrecht) – collaborating investigator
Jose Luis Diez Martin, M.D., Ph.D. (Hospital General Universitario Gregorio Marañón) – collaborating investigator
Vanderson Rocha, M.D., Ph.D. (Oxford University) – collaborating investigator
Gero Hütter, M.D., (Cellex) – collaborating investigator
$591,209
Allogeneic stem cell transplant in HIV-1-infected individuals: The first case of an HIV cure occurred in the Berlin patient, who received a stem cells transplant in Germany to treat his cancer, using cells with the CCR5 delta-32 mutation as a way to treat and ultimately cure his HIV infection. Many researchers around the world have tried, so far unsuccessfully, to duplicate this case to test which were the crucial components of the intervention – the chemotherapy, total body irradiation, genetic mutation present in the transplanted cells, and/or the graft-versus-host disease that ensued. Because the genetic mutation is most common in Europe, and because various donor screening procedures can be carried out more easily in Europe than in the United States, Drs. Martinez-Picado and Wensing and their colleagues have established a consortium of European researchers who anticipate having several HIV patients in need of stem cell transplants. They aim to try to replicate the experience of the Berlin patient, and to study differences in the HIV outcomes of patients who undergo similar versus different stem cell transplant procedures. This unique consortium presents an opportunity to learn exactly how the cure was achieved in the Berlin patient, and to use this knowledge to build interventions that could be applied more widely.
Vanderson Rocha, M.D., Ph.D. – principal investigator
National Health Service Blood and Transplant, Cord Blood Banks, Oxford, United Kingdom
Martijn Braakman, M.Sc. (Europ Donor) – collaborating investigator
Anders Fasth, M.D., Ph.D. (Sahlgrenska University Hospital) – collaborating investigator
Matti Korhonen, M.D., Ph.D. (Finnish Stem Cell Registry) – collaborating investigator
Gesine Koegler, Ph.D. (University Medical Center Duesseldorf) – collaborating investigator
Sergi Querol, M.D., Ph.D. (Programa Concordia Banc Sang I Teixit) – collaborating investigator
$126,600
Testing cord blood units for CCR5Δ32: A prospective observational cohort led by Drs. Martinez-Picado and Wensing plans to uncover and generate other cases of HIV eradication similar to the “Berlin patient.” Dr. Rocha will lead a critical adjunct to this work, namely pre-screening a large pool of cord blood stem cell donors for CCR532 homozygous and heterozygous mutations. The work will focus initially on only two cord blood banks, in Sweden and Finland, as the highest rates of CCR5 mutations are in northern Europe. They plan to include four other cord blood banks in Europe, should sufficient samples not be available from Sweden and Finland. This project also has the capacity to address a research question that could be critical to programs in other regions of the world: which donors, based on their known tissue types, have the greatest potential to harbor a CCR5
Robert Siliciano, M.D., Ph.D. – principal investigator
Johns Hopkins University, Baltimore, MD
Leor Weinberger, Ph.D. (Gladstone Institute) – collaborating investigator
$360,000
Evaluating the threat posed by intact, non-induced proviruses: In the 1990s, Dr. Siliciano and others developed a test known as the viral outgrowth assay (VOA) to measure the size of the reservoir that persists despite antiretroviral therapy. During his previous ARCHE funding, Dr. Siliciano discovered that the reservoir of HIV that persists, as measured by the VOA, may be as much as 60 times larger than previously thought. He plans to follow up these studies by characterizing more closely the additional viruses that are not measured by the traditional VOA. He will determine the extent to which drugs that are currently being tested to reactivate the virus out of latency can affect this additional pool of virus, and will work with Dr. Weinberger to describe the factors involved in determining which viruses come out of hiding while others remain latent. These studies will provide clues concerning modifications that may need to be made to current efforts to cure HIV.
Guido Silvestri, M.D. – principal investigator
Yerkes National Primate Research Center, Atlanta, GA
Daniel Douek, M.D., Ph.D. (NIH) – collaborating investigator
Jacob Estes, Ph.D. (NIH) – collaborating investigator
$180,000
Viro-immunological analyses of SHIV reservoirs in macaques undergoing aHSCT: Dr. Silvestri and his colleagues are also hoping to learn more about how the cure of the Berlin patient happened. In their approach, Dr. Silvestri infected and then stem cell transplanted three monkeys, using most but not all of the procedures performed on the Berlin patient. He will work with his colleagues to determine the extent to which the transplant procedure changed the size of the reservoir and/or the types of cells in which the virus persists and whether the transplant affected the ability of the immune system to fight the virus. As with the European study described above, the knowledge gained may provide clues to devising a cure that could be made widely available.