However, in a report that appeared in the journal Science, there is a methodology that has promise as a possible way to eradicate the presence of dormant HIV/AIDS viruses that persist in the huge population of infected individuals.
The idea is to overcome the virus’s mechanism to prevent an infected cell from recognizing its presence and self-destructing and eliminating their viral cargo in the process. “It’s actually the perfect way to kill an HIV-expressing cell,” says Peter Hunt, an infectious disease specialist at the University of California San Francisco (UCSF) who was not directly involved in the study.
The tens of millions of individuals that remain infected are kept healthy with medications that suppress viral production to a level so low they cannot be measured. However, if the intake of these drugs were to be interrupted, those viral particles that have integrated their DNA into the genes of target cells (T-Cells and Macrophages) would be quickly produced and would overwhelm the immune system.
According the author of this article, “The new cure strategy centers on one of the many internal sensors T cells and macrophages use to detect microbes. Known as CARD8, it detects key viral enzymes called proteases, which cut up other freshly minted proteins so new viruses can be assembled. When CARD8 detects a viral protease, it triggers a form of cell suicide called pyroptosis, disrupting the production of new viruses.
HIV creates its protease by joining two identical subunits into a dimer, like the two blades of scissors. And in a 2021 Science paper, a team led by virologist Liang Shan of Washington University in St. Louis (WashU) showed CARD8 can only sense the full dimer. That allows HIV to thwart the sensor by delaying the joining of the subunits until a new viral particle blebs out of its host cell. Shan’s team further showed efavirenz and rilpivirine, two existing anti-HIV drugs known to cripple a different viral enzyme called reverse transcriptase, somehow also trigger the premature dimerization of protease inside infected cells, leading to pyroptosis. No one in the field had considered them as a possible way to deplete HIV reservoir cells until then.
Priya Pal, a clinician at WashU Medicine who was a fellow in Shan’s lab, says the group has now moved “the CARD8 discovery from bench to bedside.” At the Conference on Retroviruses and Other Opportunistic Infections (CROI), she reported that the team recruited seven HIV-infected people who were fully controlling the virus with different combinations of antivirals and added efavirenz. Using assays sensitive for latently infected cells, the researchers showed that after 4 months, latent cells had declined by 20% to 50% in six of the participants.
That’s far from what is needed to cure a person, Shan stresses, but it’s proof of principle that tripping the CARD8 alarm can help. The result “calls for the development of more potent protease activators,” says Shan, who last year moved his lab to the Shenzhen Medical Academy of Research and Translation.
Several drug developers are already hunting for these more potent drugs, a class called targeted activator of cell kill (TACK) molecules. Merck reported in Science Translational Medicine in 2023 that it had found a compound that is “an order of magnitude” more potent than efavirenz at dimerizing protease, which it has turned into a candidate drug. The company is now evaluating its safety and activity against HIV levels in previously untreated people, a first step before assessing its impact on latent-cell reservoirs in people who are already controlling the virus with standard drugs.
Ho is testing a one-two punch strategy that combines a related TACK with an established—but so far unsuccessful—approach to depleting those reservoirs. For 20 years, researchers have attempted to eliminate reservoir cells by prodding them with “latency reversal agents” (LRAs) that spur viral replication. The idea was that the immune system would then destroy those cells or they’d rupture. But few LRAs used in this “shock-and-kill” approach have had any impact on reservoir size.
In one of many attempts to create better LRAs, Ho’s lab has developed an antibody designed to target latently infected T cells and trigger cellular signals that spur the virus to replicate. In lab tests with immune cells from people living with HIV who are on treatment and fully suppressing the virus, the antibody alone didn’t eliminate all the latently infected cells. But Ho reported at CROI that when they added the TACK drug, the levels of viral RNA steeply plummeted, indicating pyroptosis had further depleted the reservoir. “This TACK story is amazing,” says Steve Deeks, a UCSF researcher who specializes in HIV cure studies and contributed to the Shan team’s new study.
Ho stresses that LRAs plus TACKs may not need to eliminate reservoirs to have a major impact on HIV infections. “The question is, what happens if you reduce the reservoir size by 1000-fold?” he asks. This may be enough to allow people who stop taking anti-HIV drugs to control what little virus is produced with their immune responses, a so-called functional cure.
Hunt suggests TACK drugs may also help abrogate serious long-term health problems caused by HIV that still afflict people who fully suppress the virus with drugs. Even in latently infected cells, the virus continues to copy itself at low levels, leading to a chronic state of inflammation that, over the years, increases the risk of cardiovascular disease, cancers, and organ failure. “The cure field right now is thinking about TACKs as strategies to reduce the reservoir load, but I see these molecules as potentially having a more direct, earlier effect on inflammation,” Hunt says. “It could be very important.”
These results, although preliminary, may lead to strategies that can effectively control the production of virus to such a low level that the immune system can readily handle it. If successful, this approach would have a profound impact upon global health.
