amfAR, the Foundation for AIDS Research, this week announced substantial new grants for research designed to determine whether a cure for HIV infection is possible.
“amfAR has a long history of funding breakthrough research, and developing this consortium gives me great hope that we will catalyze the research for a cure for HIV/AIDS,” said amfAR CEO Kevin Robert Frost. “We believe that a collaborative research effort has the potential to dramatically accelerate the search for a cure.”
The initial round of funding for the newly constituted amfAR Research Consortium on HIV Eradication (ARCHE) includes projects in each of three areas that are widely considered central to HIV eradication:
- The search for a sterilising cure that would eliminate all HIV from the body;
- The search for a functional cure that would achieve permanent viral suppression without therapy; and
- The characterisation of viral reservoirs, the barrier that must be overcome to achieve a cure.
“There is a growing sense within the scientific community that the search for a cure for AIDS is ripe for a concerted research effort,” said Dr. Robert Siliciano, a researcher at Johns Hopkins University whose amfAR-funded study will focus on the potential to eradicate HIV.
“We hope that both the research that our team will conduct, as well as this new collaborative research framework, will speed that process,” said Dr. Siliciano, who will collaborate with Dr. Janice Clements, also of Johns Hopkins University.
Because HIV can persist indefinitely in reservoirs in an infected individual, eradicating HIV will require flushing virus out of those reservoirs and then targeting it with antiretroviral therapy.
Developing new therapeutic agents, such as ones that might flush out latent HIV, can be a timely and costly enterprise, so Drs. Siliciano and Clements are hoping to identify drugs that are already FDA-approved and available for the treatment of other conditions that could be used in the context of HIV infection.
They already have one promising lead that they plan to test, both alone or perhaps in conjunction with other agents. These drugs will be tested in two different test-tube settings, one that simulates latent infection in reservoirs, and the other using infected cells that have been extracted from HIV positive patients.
In addition, they will use non-human primates to test whether such agents might reduce the amount of virus that is growing or the number of cells that are harboring latent HIV. This model will also allow them to test whether and how latently infected cells throughout the body are affected by such drugs. If successful, these studies could point the way to strategies that could shorten the development time of interventions to cure HIV infection by ten or more years.
A series of studies to be undertaken by Dr. Sarah Palmer of the Swedish Institute for Infectious Disease Control and Karolinska Institutet will aim to determine which cellular reservoirs are most responsible for the persistence of HIV and the extent to which these reservoirs could be disrupted by anti-HIV drugs. Dr. Palmer will collaborate with Dr. Frederick Hecht.
Dr. Palmer will work with Dr. Hecht to analyse HIV found in blood and tissue samples of patients who initiated antiretroviral therapy either during acute HIV infection or later.
Their goal is to identify which cells produce the virus that is routinely measured in plasma, virus that persists despite very effective antiretroviral therapy. Genetic sequences of plasma viruses will be compared to the sequences of viruses isolated from peripheral blood cells, cells in the gastrointestinal tract, and the bone marrow. This study will help define where the persistent plasma virus is being produced.
Dr. Joseph McCune of the University of California, San Francisco, collaborating with Dr. Steven Deeks, will examine the role of ongoing activation of the immune system—long suspected of playing a role in HIV disease—in the ability of HIV to persist for the lifetime of an infected patient.
They hypothesise that a self-perpetuating, looping chain of events is established soon after HIV infection first occurs. The immune system is activated as it attempts to combat the infection, but this immune activation in turn fuels the ability of the virus to replicate and persist, resulting in a situation in which immune activation and viral replication feed one another.
One enzyme that has been shown to be associated with AIDS progression is IDO, and Drs. McCune and Deeks believe it may play a critical role in maintaining the positive feedback between immune activation and viral growth. They will test whether disrupting this enzyme reduces the level of immune activation, which would in turn result in a decrease in viral persistence.
They will also determine whether patients who naturally maintain extremely low levels of virus also have naturally low levels of IDO. If their hypothesis is correct, the results will point to a potential new therapeutic strategy that could both decrease levels of immune activation— itself associated with some of the disease conditions commonly seen in HIV infection— and lower the amount of virus that persists, bringing us closer to a functional cure.
Dr. John Zaia of the Beckman Research Institute of City of Hope, in a study that delves deeper into the circumstances of a leukemia patient in Berlin who appears to have been cured of HIV, will examine the possibility that cancer chemotherapy can perturb reservoirs of HIV, a study that could provide clues for the development of therapeutic interventions to cure HIV.
Recently, an HIV patient in Berlin who also had acute leukemia underwent a stem cell transplant from a donor who had a genetic mutation that rendered that donor—and now the patient—resistant to HIV.
The extent to which the chemotherapy prior to the transplant may have contributed to the presumed cure is not known, so Dr. Zaia will use a sensitive assay that can measure extremely low levels of virus in patients with AIDS-related lymphoma who have been treated with either partial or aggressive chemotherapy. If cancer chemotherapy can perturb reservoirs of virus, it may provide clues for the development of future therapeutic interventions to cure HIV.
“amfAR has a long and successful history of bringing people together to take on the big challenges of HIV/AIDS,” said Dr. Rowena Johnston, amfAR’s vice president and director of research. “We’re tremendously excited by this consortium. And we’re confident that this collaborative approach will create a synergy that produces results that exceed what can be generated in individual laboratories.”
amfAR’s commitment to a cure for HIV/AIDS is consistent with comments recently made by Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases at the National Institutes of Health, the lead agency on federally-supported AIDS research. Describing research towards a cure as “high risk but very high impact,” Dr. Fauci continued: “I feel strongly that this is a direction we should go, even though years ago this would have been unimaginable.”