When therapeutics battle HIV, they tend to miss pockets of resistance where HIV can hunker down until it stages a comeback. HIV, then, cannot be defeated until its remnants are roused to action, and its hiding places exposed and eliminated. This two-step strategy is called “shock and kill.” It sounds promising, but shock and kill hasn’t quite worked yet. It still needs the right shock.
Encouragingly, a better shock has been proposed by scientists at Sanford Burnham Prebys Medical Discovery Institute. These scientists, led by Sumit Chanda, PhD, director and professor and Nicholas Cosford, PhD, deputy director of the NCI-designated Cancer Center at Sanford Burnham Prebys and co-senior author of the study, have identified a drug that reawakens the virus without activating the immune system. That is, the drug makes it possible to save the immune system without having to destroy it.
“What scientists have found with other ‘shock’ approaches is that they can be too hot and overactivate the immune system, or too cold and don’t wake up the virus,” said Chanda. “Our research identifies a drug that works in the ‘Goldilocks’ zone.”
The drug is a Smac mimetic called Ciapavir (SBI-0953294). Smac mimetics are a class of small-molecule peptidomimetics derived from a conserved binding motif of Smac (second mitochondria-derived activator of caspases), an endogenous protein inhibitor of apoptosis. Originally developed as cancer drugs, Smac mimetics are being evaluated for other purposes, such as fighting HIV.
Repurposed Smac mimetics have had modest success in reversing HIV latency. In hopes of building on this success, Chanda, Cosford, and colleagues decided to experiment with a Smac mimetic optimized to reverse HIV latency. The results of this work appeared June 23 in Cell Reports Medicine, in an article titled, “Pharmacological Activation of Non-canonical NF-κB Signaling Activates Latent HIV-1 Reservoirs In Vivo.” According to this article, Ciapavir is more efficacious as a latency-reversing agent than other drugs of its class.
“[Ciapavir] induced activation of HIV-1 reservoirs in vivo in a bone marrow, liver, thymus (BLT) humanized mouse model without mediating systemic T cell activation,” the article’s authors wrote. “This study provides proof of concept for the in vivo efficacy and safety of Ciapavir and indicates that Smac mimetics can constitute a critical component of a safe and efficacious treatment strategy to eliminate the latent HIV-1 reservoir.”
This research builds upon the scientists’ previous discovery that Smac mimetics—which have undergone human safety testing and are currently in clinical trials for certain cancers—can reactivate latent virus in cells from people with HIV undergoing antiretroviral therapy. In parallel, scientists are exploring ways to kill the reactivated virus—such as developing broadly neutralizing antibodies or modified T-cells (CAR-T cell therapy) that destroy infected cells—which would complete the “shock and kill” strategy.
In this study, the researchers administered Ciapavir to mice with a human immune system and were infected with HIV. The treatment significantly increased levels of HIV in the blood and bone marrow—indicating that the latent virus was activated. Importantly, immune activation was minimal. Overactivation of the immune system can be deadly and has historically been a problem with the “shock and kill” approach.
“Ciapavir is the first Smac mimetic specifically optimized for an HIV cure, so it is significantly more potent for HIV than other molecules in this class,” said Cosford. “As a result, Ciapavir may be effective when used on its own instead of in combination with a second drug, as our previous research showed, and potentially at lower doses.”
The researchers call Ciapavir a bivalent, next-generation Smac mimetic compound. To arrive at Ciapavir, the researchers began with SBI-0637142, a monovalent Smac mimetic compound that showed more potency as a latency reversing agent (LRA) than bivalent Smac mimetic compounds, even though bivalent compounds are generally stronger LRAs. Ultimately, the researchers developed a bivalent structure based on SBI-0637142. They found that the result, Ciapavir, exhibits substantially greater potency and efficacy as an LRA, inducing comparable levels of latency reversal at concentrations 10- to 1,000-fold lower than SBI-0637142, the first-generation molecule, without an increase in cytotoxicity.
Ciapavir activates noncanonical NF-κB signaling in CD4+ T cells, the target of HIV. This lesser-used pathway activates only a subset of the immune system—which is the key to the drug’s gentle approach.
“Noncanonical NF-κB signaling is part of the immune system’s ‘plan B’ response to pathogens,” explained Lars Pache, PhD, research assistant professor in the Chanda lab and first author of the current study. “In this case, we are using this alternate pathway to our advantage. We can wake up the virus without overwhelming the immune system.”
Ciapavir will next undergo further evaluation in nonhuman primates, as well as additional toxicology studies to ensure that the drug is ready for testing in humans.