The Work Ahead
Announced on World AIDS Day 2015 and launched with a $20 million grant to the University of California, San Francisco, the amfAR Institute for HIV Cure Research is up and running. A truly collaborative enterprise, the Institute’s work will be overseen by an executive committee comprised of Institute Director Paul Volberding, M.D., Ph.D., the principal investigators (see below), and amfAR’s Director of Research Rowena Johnston, Ph.D. The work will be divided into four modules—C, U, R, E.
MODULE C: Chart
KEY QUESTION—Viral reservoirs: in which cells, in which tissues, in which people?
Principal Investigator: Mike McCune, M.D., Ph.D.
In this module, Dr. McCune and his colleagues will look at which tissues in the body harbor reservoirs of persistent HIV. They’ll be looking in particular at tissues in various regions of the gut and the female reproductive tract and comparing them with blood. By carefully examining the tissues’ genetic information, both DNA and RNA, the researchers will get a sense of whether or not the virus is present and in which relative amounts in each area.
They will also look at which types of immune system cells in those tissues harbor the virus. In addition to what scientists believe to be the main reservoir, central memory CD4 T cells, what about macrophages or other types of T cells?
A critical question they will address is whether the HIV in these cells is capable of replicating. Since HIV mutates over and over again, in many instances errors occur in the virus’ DNA that render it incapable of forming an infectious virus. The researchers will use cutting-edge digital PCR technology to look at individual cells for defects in the viral genome.
They will also examine the effects of age, sex, and the timing of ART initiation on the size, location and composition of the reservoir.
Finally, they aim to determine the effects of different experimental cure interventions in each cell subset and tissue of interest, and compare them across the various populations of HIV-positive people.
MODULE U: Understand
KEY QUESTION—How to reverse latency and kill infected cells?
Principal Investigator: Warner Greene, M.D., Ph.D.
Researchers at the Institute will pursue variations of the ‘shock and kill’ strategy, which aims to awaken, or shock, HIV out of its latent state so that the cells harboring it can be targeted for killing by elements of the immune system. Dr. Greene and his team will test a number of ‘shocking’ agents that could potentially harness the body’s innate immune system in order to awaken and possibly even kill persistently infected cells.
The researchers will focus their efforts on so-called toll-like receptors (TLRs), a class of proteins that play a key role in the innate immune system. They will test several drugs that can act on the receptors, TLR agonists, alone and in combination, in blood and tissue for their ability to reactivate virus. They will then explore the mechanisms of action of those agents that are able to reactivate virus: do they exert their effects directly or indirectly? If indirectly, via which types of immune cells? Can simpler and more specific means of delivering the same effects be devised?
The innate immune response is one of two main arms of the immune system. It delivers an immediate and potent, if unspecific, counterattack against infectious agents. By contrast, the adaptive immune response, the second arm, provides long-lasting protection by creating memory of specific invading pathogens that can be quickly recalled during subsequent encounters.
The team will then look at other classes of latency reversing agents (LRAs), such as HDAC inhibitors, BET inhibitors, and so-called noise enhancers, to see if they could be used to boost the effectiveness of TLR agonists. Antibodies and other agents will be tested for their ability to kill infected cells that have been reawakened.
MODULE R: Record
KEY QUESTION—How much virus is in the reservoirs?
Principal Investigator: Satish Pillai, Ph.D.
In this module, Dr. Pillai and colleagues seek to answer the question: How can we determine if our cure-designed therapies are having a meaningful impact on the persistent HIV reservoir? The case of the Mississippi baby demonstrates how critical a question this is. In 2013, this child, born with HIV, was believed to have been cured after being off antiretroviral therapy for more than two years. But the child eventually experienced a resurgence of HIV, proving that the available tools were simply not sensitive enough to detect virus that was present all along.
Dr. Pillai and colleagues will take several approaches to assessing the size of the reservoir using a range of cutting-edge technologies. One of the challenges the researchers face is that the vast majority of HIV, having mutated and made imperfect copies of itself, is incapable of replicating. So they will work on methods of accurately differentiating between replication-competent virus and virus that is disabled and poses no threat. For example, they will sequence the virus and measure its ability to produce RNA or proteins. Detection of either one will suggest that a given virus is replication competent.
They will examine HIV antibodies in the blood. Since these antibodies form when HIV is present and active in the body, they may provide an indication of whether and how much virus is present in tissues as well as in the blood.
And the researchers will use medical imaging techniques including PET and CT scans to directly visualize the presence and distribution of persistently infected cells. These technologies have the advantage of being non-invasive and give researchers the ability to scan the whole body and take a snapshot of the relative burden of virus in tissues throughout the body.
MODULE E: Eradicate
KEY QUESTION—How to safely eliminate the virus from the reservoir?
Principal Investigator: Steve Deeks, M.D.
This module will draw on knowledge gained in all of the other modules and will bring to bear the advanced techniques and technologies deployed and refined by all the collaborating research teams. Drawing all of these strands together, Dr. Deeks and his team will test the effectiveness of a range of interventions in human clinical trials.
For example, the researchers will examine the effectiveness of TLR agonists, both alone and in combination, on the persistent reservoir and will also conduct a small clinical trial of a vaccine called GEO-D03, which also has a TLR component, in 30 individuals with HIV. Using highly sensitive tests, including the assays employed by Dr. Pillai and his group, the trial participants will be tested periodically for evidence of reactivated cells and of decreases in the size of the reservoir. Information derived from Module C (see above) will guide their search for persistent virus in tissues and cells.
They will conduct another clinical trial of TLR agonists in collaboration with researchers at the Infectious Disease Research Institute (IDRI). This will involve reformulating these agents for nanoscale delivery by injection in six monthly doses. Information gained from Module U will help them understand the mechanisms by which the agents work. Understanding these mechanisms could help researchers fine-tune their interventions to make them even more effective.
They will also perform additional analyses of patients participating in several clinical trials of latency reversing agents and/or immune interventions that are currently underway.
The amfAR Institute is a collaborative enterprise whose primary partners are UCSF, the Gladstone Institute of Virology and Immunology, and Blood Systems Research Institute. Additional collaborating institutions include the Infectious Disease Research Institute, Oregon Health and Science University, University of California, Berkeley, and Gilead Sciences. Expressing his optimism and his faith in the outstanding researchers under his command as director of the amfAR Institute, Dr. Volberding said, “We are dedicated to leading the way to a cure and believe our history, organization, resources and partners will allow us to remain at the forefront in this crucial final chapter of the HIV epidemic.”