Researchers have uncovered that a new drug class can be tapped to purge dormant HIV from a patient's body, wiping out the virus completely once and for all.
Antiretroviral treatments have made it possible for patients to live with HIV for years. Unfortunately, despite being well enough, they still harbor small pockets of cells that give the virus a hiding place. HIV genes reside within cells but their genetic code isn't read so they don't make proteins that triggers the immune system to respond. However, when patients are taken off antiretrovirals, the dormant cells reactivate and produce the virus, re-establishing the disease.
"The key for a cure for HIV is to purge these cells that have dormant HIV," said Lars Pache, Ph.D., the lead author for a study published in the journal Cell Host & Microbe.
Reactivating cells infected by dormant HIV to kill the virus is called a shock-and-kill approach. The approach, however, has not been fully explored because the drugs used so far, called latency reversing agents (LRAs), reawaken the virus but are either not potent enough to kill it or trigger a massive reaction in the immune system that in itself could be fatal.
Instead, Pache and colleagues are using a drug class known as Smac mimetics, tapping into a cell pathway, a molecular backdoor that can act like an alarm that wakes up the HIV virus without alerting the immune system. They also looked for host cells that can aid in suppressing the virus and found that the absence of the BIRC2 gene led to a spike in HIV activity. Smac mimetics work by interfering with the functions of BIRC2 and molecules related.
Specifically, SBI-0637142, a potent BIRC2 inhibitor, was identified. It is about 10 to 100 times more potent than current LRAs and is particularly suited for HIV-1 treatment so it is a promising candidate for addressing dormant HIV cells.
One of the reasons HIV genes can hide within cells is that they can cover themselves with tightly spun DNA. Histone deacetylase inhibitors, a class of drugs, can unfurl the DNA but most of the inhibitors developed have not been effective in reactivating dormant HIV on their own. However, in combination with Smac mimetics, they might work better.
The researchers were mostly concerned with whether or not they would be able to reactivate dormant HIV within the cells of a patient taking antiretrovirals. They combined a histone deacetylase inhibitor called panobinostat with SBI-0637142 and saw that HIV was reactivated without triggering a response from the immune system.
Pache and colleagues are now hoping to team up with a pharmaceutical company to develop the molecules for further evaluation, moving into human clinical trials once criteria for safety and efficacy are met.
Photo: NIAID | Flickr
