Research on SMYD2 shows potential to wake up the HIV reservoir
by Chael Needle
HIV latency—where HIV hides out in reservoirs, dormant and beyond the reach of antiretrovirals—has become a primary focus of research as attention has turned more and more toward a cure. A functional cure would mean the virus is controlled if an individual goes off anti-HIV meds for extended periods of time. But we know that if an individual stops combination antiretroviral therapy, the virus in the T cells (and other sites) that make up the reservoir wakes up and, thus, actively replicating HIV is back in business. What is needed, ultimately, is a sterilizing cure—complete eradication of replication-competent virus from the body.
The “shock and kill” concept has been developed as one potential strategy to target HIV reservoirs—shock latent, replication-competent HIV with a combination of drugs into a wakeful state and then kill it, with the help of the body’s own immune system.
But how might we accomplish this?
Researchers have had limited success in efficiently interrupting the regulation of viral latency and waking up the dormant HIV, but that may have now changed.
SMYD2 (one of a class of enzymes called methyltranserases that have become a focus of cancer tumor research) has been discovered to regulate latency in infected HIV-1 T cells, in vitro. Inhibiting SMYD2—stopping it from doing its essential work of preserving latency—means that HIV becomes a reachable target once again. Researchers at Gladstone Institutes, led by Melanie Ott, MD, PhD, a senior investigator at Gladstone and a professor in the Department of Medicine at the University of California, San Francisco (UCSF), have completed a study that produced new insights into how latency works via interdependent mechanisms and established SMYD2 as a potential therapeutic target. In collaboration with Warner Greene, MD, PhD, senior investigator and director of the Gladstone Institute of Virology and Immunology, researchers tested small molecules in preclinical development as possible SMYD2 inhibitors and found success.
Results of the study that established SMYD2 as a target were published in a recent issue of Cell Host & Microbe (May 10, 2017) by Ott et al. “Our findings provide the basis for a new model of HIV latency wherein SMYD2 contributes to durably repressing the latent virus,” said Dr. Ott, in a prepared release. “They also underscore the emerging ties between cancer and HIV treatment through shared pharmacological targets. Though we are still far from a human application, it is exciting to know that data from this study might readily connect with clinical efforts.”
A&U had the opportunity to correspond with Rowena Johnston, PhD, Vice President and Director of Research at amfAR, which helped to fund this research through its Institute for HIV Cure Research as part of its initiative to find a broadly applicable cure by 2020. In the following interview, Dr. Johnston discusses the knowns and unknowns of SMYD2 and HIV latency.
Chael Needle: Could you please tell our readers more about the previous cancer-related research that led to the decision to focus on methyltransferases?
Dr. Rowena Johnston: Two of the fundamental problems in cancer involve (1) a dysregulation of the cell cycle—in cancer, the cells divide and grow out of control, instead of regulating and controlling their own cell cycle the way healthy cells would; and (2) signals that instruct a cell to commit suicide—in a healthy person, a cell that detects that some process inside it has gone disastrously wrong would initiate a suicide program and self-destruct. These processes—regulation of the cell cycle, and programmed cell death—are regulated by genes that cancer researchers noticed are themselves (dys)regulated by SMYD2. On this basis, a couple of companies developed molecules that would inhibit SMYD2 and thus presumably normalize these processes in cancer. They are still testing these compounds, which to my knowledge have not yet entered clinical trials and are not yet used in clinical practice.
It’s interesting that many of the concepts and hurdles that cancer researchers are fighting are similar to those faced by HIV researchers, and that some of the tools to overcome these hurdles might end up sharing many of the same properties.
If something like an SMYD2 inhibitor could be formulated as an agent that reactivates latent cells, what is Step 2? Do we need to know more about how fast to wake up cells, for instance? Or do we need to account for other factors that preserve latency? Or do we need to establish what “kill” agents are best once the reservoir is activated?
There’s no question that the “kill” part of the “shock and kill” approach is critical. As Warner Greene (a co-author on this paper) often says, “shock without kill is a failed strategy.” If, and it’s a big if, we assume a few things—that the SMYD2 inhibitor is safe and reactivates every pathogenic virus—it might be reasonable to hypothesize that many, maybe even most, of the cells harboring the reactivated cells will die by the process of virus production itself. But almost nothing in biology is 100-percent, so it’s more likely that even the most successful drug will not reactivate every latent virus, or that every cell harboring a reactivated virus will die, in which case we will need to add a mechanism to increase the chances of killing reservoir cells. Most researchers working on this component are pursuing some form of immune-based therapy, such as a vaccine or antibodies. Interestingly, other immune-based strategies HIV researchers are interested in come from the cancer arena too, such as immune checkpoint blockers or CAR [chimeric antigen receptor] T cells.
Do we know if SMYD2 is better equipped for certain reservoir sites or cell types?
At this point there are quite a few unknowns. So far the researchers have demonstrated that SMYD2 inhibitors by themselves will likely not reactivate latent HIV, and will need to be combined with other drugs. Depending on what those other drugs are, or the mechanisms involved in reversing latency with the drug cocktail, it’s possible some latent viruses will be reactivated more easily than others. They report here that SMYD2 is a promising lead in cells from the blood, but so far we don’t know if the same holds true for tissues such as lymph nodes, which is where the great majority of latent virus hides. It’s also possible that the virus is latent in cells other than T cells, for example macrophages, and if true it would be important to know whether any drug or combination flushes latent virus out of all reservoir cells, or only some fraction of them.
As individuals living with HIV and on treatment are living longer, do we know if or how the HIV reservoir changes over time? That is, do we know if it evolves—weakens, intensifies—or does it seem steady in the presence of consistent effective anti-HIV meds? Ultimately, does the reservoir present a stable or moving target, and how would this affect anti-latency efforts?
In terms of size, the reservoir seems to be fairly stable as far as we can tell, but the picture is a lot less clear in terms of the particular virus species that constitute the reservoir. Recent evidence suggests that an increasing proportion of the reservoir might be made up of viruses with lethal genetic mutations, for example, although the number of viruses that are capable of causing disease remains formidable. And although the viruses themselves may accumulate mutations, it’s unclear whether the mechanisms that maintain them in a silent state change over time. It’s this latter factor—the collection of mechanisms behind the silencing—that is the target of SMYD2 and other latency reversing agents.
Do different reservoirs have different qualities? For example, is there a difference between a reservoir formed when HIV is left untreated for long periods vs. a reservoir formed in an individual on treatment after infection? If so, how does this shape the development of anti-latency agents?
Related to the previous answer, new data suggest that the reservoir of a person who starts antiretroviral therapy soon after infection may accumulate mutations at a different rate than a person who starts treatment after having been infected for a long time, but it’s not clear to me what the differences might be in terms of reversing latency. In other words, the mechanisms that maintain the virus in a silenced state might not be related to the degree or type of accumulation of mutation, for example. There is certainly a lot to learn about the extent to which there may be individual differences in mechanisms that maintain the viral reservoir in one person versus another.
What questions remain and what is the next step in this research?
The amfAR Institute for HIV Cure Research, under whose auspices this research was conducted, has chosen to focus their efforts on shock and kill as a way to cure HIV. The crux of this strategy is to find agents that can reverse latency, and ways to ensure the killing of cells that harbor reservoir virus. So far, no single drug that is also safe has been found that can reverse latency, so researchers aim to find optimal drug combinations that can force latent virus out of hiding. This SMYD2 finding is interesting on a couple of fronts—the researchers have identified a new class of agents that has the potential to be combined with drugs we already knew to have a partial effect. This allows researchers to test the idea that simultaneously attacking HIV latency from a variety of angles will be more effective than simply making one drug stronger, which may be associated with toxicity. Second, the fact that there already exists a development pathway for SMYD2 inhibitors means that if these drugs are effective as part of an approach to cure HIV, they may be available to test in people more quickly than if we had to start from scratch. We should acknowledge though that, at the same time researchers are working on developing the optimal latency reversing agents, one of the big unknowns in HIV cure research is the other side of the coin, namely how best to mop up any remaining infected cells.
Most HIV cure researchers would acknowledge that we have a lot of hard work yet to do, but there are a lot of smart scientists developing and testing a range of ideas that didn’t exist just a few years ago.
Chael Needle is Managing Editor of A&U. Follow him on Twitter @ChaelNeedle.