The amfAR Institute for HIV Cure Research aims to determine whether the immune system can be strengthened so that it can either destroy all HIV-infected cells in the body or control the virus after antiretroviral therapy is stopped. This will likely require a combination of interventions, including a vaccine and drugs that help to make vaccines work better. A popular partner is the “TLR agonists,” which act to improve the immune response’s capacity to seek out and target anything foreign, including HIV. These partner drugs are often called “vaccine adjuvants.”
In recognition of HIV Vaccine Awareness Day on May 18, amfAR’s director of research, Dr. Rowena Johnston, spoke with Dr. Steve Deeks, a lead investigator at the Institute, about combining old and new ideas around vaccines and their adjuvants to design a cure for HIV.
The Institute will start by investigating the use of TLR agonists as part of a cure strategy. Why is the group focusing on these drugs?
TLR agonists are exciting because they do two things. First, they indirectly activate CD4+ T cells, the preferred hiding place for HIV during antiretroviral therapy. This forces the virus out of its hiding place and allows the immune system to see the virus and its reservoir. Second, they enhance immune function and hence may lead to the generation of a powerful army of HIV-specific killer T cells. We therefore believe these agonists might simultaneously contribute both “shock” and “kill” in the context of a “shock and kill” strategy, which many believe to be the most effective way to achieve a cure.
Would you anticipate that TLR agonists alone might be able to cure HIV?
It would be great if they could, but I doubt they will work alone. Still, it is possible that a durable remission might be achieved at least in some people. The nature of science is that you never know until you do the experiments, and we are designing those studies. In all likelihood, though, this promising class of drugs will be combined with other approaches, particularly vaccines.
Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system, detecting and defending against foreign invaders. The innate immune response delivers an immediate and potent, if unspecific, counterattack against infectious agents. TLR agonists are drugs that can act on these receptors, reactivating persistent virus in blood and tissue.
Therapeutic vaccines have not been very successful against HIV to date. What makes you think this might be different?
Our main source of enthusiasm for using TLR agonists comes from two small studies done in monkeys by a group in Boston working with Gilead. Those researchers put monkeys infected with SIV (the monkey equivalent of HIV) on antiretroviral therapy (ART) to get the virus under control. These treated monkeys share much in common with treated people. The researchers then gave the monkeys a TLR 7 agonist that was initially developed for the treatment of hepatitis B. The TLR agonist caused frequent viral “blips,” suggesting that it worked as a powerful shock agent. More importantly, when ART was stopped, the virus was at least partially controlled, suggesting that the immune system had indeed been made stronger. That means we have a proof-of-concept that by using a TLR7 agonist, we can enhance the function of the immune system such that it can control SIV, and perhaps by extension, HIV in people.
As these monkey studies were being done, our group in San Francisco was collaborating on another study of a vaccine. This vaccine turned out to have the potential to stimulate TLRs via another mechanism. We saw in this study some evidence that the virus was being shocked out of its hiding place.
Another reason for optimism comes from an ongoing study conducted in Denmark. Unlike the monkey studies, they are using a TLR9 agonist. I’m not at liberty to disclose full results for now, but we are encouraged by what we’ve seen of those data so far. In fact, one member of the Danish team, Dr. Martin Tolstrup, is spending six months working with us in San Francisco and is lending a lot of advice and insight as we ramp up our own efforts. And in April a test-tube study was published suggesting that a TLR2 agonist works as an effective HIV shock agent. So, data from a number of different sources seem to be coming together to suggest that TLR agonists are a promising avenue.
Shock and Kill
During the course of HIV infection, cells producing virus dot their outer surface with viral proteins that act like flags to the immune system signaling infection. Once the ‘flags’ are recognized by the immune system the cells are killed. The cellular reservoir of persistent virus, however, is effective at hiding from the immune system because these cells do not produce enough virus to post the flags on their surface. The shock and kill (or kick and kill) approach aims to shock the reservoir out of hiding by using the right drug combinations to activate the persistent virus. This will lead to flagging of the cell’s outer membrane, alerting the immune system and facilitating killing of the cell.
Is progress on a therapeutic vaccine for HIV likely to have any bearing on the search for a preventive vaccine?
In all likelihood this will go in the opposite direction. Over the past two decades there has been massive investment in the development of a preventive HIV vaccine, from NIH and others. Most of these vaccines have not worked, but we’ve learned a lot about how they should work and why HIV is so challenging to develop a vaccine against. The knowledge gained from those studies can be applied directly to the search for a therapeutic vaccine. Some of the candidates that have been tested came directly from the prevention field. So I think prevention will lead the way, but we have to acknowledge up front that treatment is different and that we may end up needing something different.
If TLR agonists do what you hope they will, they will likely be boosting the immune response via a variety of cells. Why is it important to know exactly which immune cells are being boosted?
You could take two approaches. In the black box approach, you have an intervention that has some effect but you have no idea how that happened. That’s the empiric approach. Historically, that’s how vaccines have been developed. That’s fine if you get lucky and your intervention worked, but we probably won’t get lucky. I suspect in the initial studies we may find that some people do well and some don’t do as well. Knowing more details about what happened to which cells during the intervention allows us to design more specific and improved products in the future.
You lead the clinical module of the amfAR Institute for HIV Cure Research, which means that when you get promising candidates to test, you’ll be leading the clinical trials. What might be some of the pluses or minuses of using TLR agonists in humans?
The main advantage is that they are powerful adjuvants and they are known to enhance the capacity of other vaccines to work. This has been shown repeatedly in animal models and in people, so there’s a robust scientific rationale. There is also robust safety data suggesting this approach will do no harm.
The downside is that TLR agonists probably won’t work on their own, which means we’ll have to search for a partner intervention. Also, if we take a look at the shock and kill approach, we know we’ll want to shock the virus out of hiding throughout the body, which means we have to find a way to deliver these agents systemically. Right now TLR agonists are delivered as a shot in the arm when they’re used as a vaccine adjuvant – this works well to generate immune responses at the site of the injection, and those immune responses can migrate throughout the body. But shocking the virus will require that these drugs act globally, with the potential that there may be more toxicity.
What are some of your other plans for clinical studies at the Institute?
The Institute is focused squarely on TLR biology, and TLR agonists 4, 7 and 9 are our lead candidates. One part of our effort is focused on how to get these drugs to effectively shock HIV, and the other part of the effort is on maximizing the kill aspect. By the end of five years we will have developed a robust database on how they work. In case they don’t work by themselves, though, we are pursuing several other lines of investigation. For example, there is the potential for various vaccines to work in concert with these agonists.
There is also a lot of opportunity to learn from the cancer field. In both HIV and cancer, we know that the ongoing efforts of the immune system to clear the infection, or the cancerous cells, lead to chronic inflammation that interferes with the ability of vaccines to work. We want to develop approaches to modulate the activity of the immune system so it no longer gets in the way of our treatment. Some of the ways we’d like to test this come directly from the cancer field using drugs like rapamycin, for example.
Another approach in cancer that might be very useful in HIV is to use immune checkpoint blockers. Immune checkpoints are signals that appear on immune cells as a way to keep inflammation in check. Because of the chronic inflammation in HIV, the immune system tries to put the brakes on the system so that the inflammation does not rage out of control. This also happens in cancer, and cancer scientists have developed classes of drugs that can reverse these brakes so that the immune system can fight the cancer more effectively. We are hopeful that immune checkpoint blockers will help TLR agonists to work better.
To determine if any of these approaches work, we have to improve our methods for measuring the virus where it hides, which is largely in lymph nodes. The Institute is also developing new assays and imaging approaches so we can measure what kind of impact our clinical interventions are having.