Daily Archives: June 24, 2020
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.”