HIV may no longer be a death sentence thanks to sophisticated drug therapies, but a cure continues to elude scientists. One of the main reasons we have yet to achieve this goal is the virus’ frustrating ability to lay low in cells, forming so-called “latent reservoirs” that evade both the immune system and antiviral agents.
Encouragingly, scientists may have just stumbled upon a novel way to awaken these pools of dormant HIV, and the compound in question is already FDA-approved. The discovery suggests it may ultimately be possible to use combinations of drugs that not only suppress HIV, as is currently possible, but also eradicate the lingering sources of virus that have so far represented a barrier to the development of a cure.
“We’ve made great progress, but at the end of the day you still have more than 30 million people walking around with HIV,” lead author Satya Dandekar from the University of California Davis said in a statement. “Without drugs, the virus can come back at the same threat level for patients. Eradicating HIV is extremely critical.”
Currently, anti-HIV drugs are very good at blocking the replication of HIV, so much so that they can reduce the viral load in the blood to the point where it is undetectable by traditional tests. But there is a major stumbling block in that they are only capable of targeting actively replicating HIV, meaning they are useless against cells containing latent virus concealed within resting cells. So as soon as an infected individual stops treatment, the virus comes bounding back with a vengeance.
With this in mind, scientists are working toward a so-called “shock and kill” approach of viral eradication, in which they drive out dormant HIV from its resting place and then attack it with drugs that effectively prevent it from copying itself. But achieving this has been no mean feat: Scientists must first find a substance capable of arousing HIV but without inadvertently overstimulating the immune system.
The UC Davis team, however, think they could be on to a winner. They honed in on a molecule called PEP005, which is the only active component of the FDA-approved anticancer drug PICATO. This molecule displayed a remarkable ability to reactivate latent HIV in blood samples obtained from HIV patients and exerted no significant toxic effects to the cells, the researchers describe in PLOS Pathogens. Further analysis revealed the mechanism of action, which was through activation of a signaling pathway involving a cellular molecule called NF-κB. This complex of proteins can bind to HIV’s genome and subsequently drive replication.
Armed with the knowledge that one drug is rarely sufficient to tackle HIV due to its high mutation rates, the scientists searched for other compounds capable of exerting similar effects. Ultimately, they found another molecule, called JQ1, which appeared to work synergistically with PEP005. When combined, the level of activation was up to 15-fold greater than PEP005 alone.
Encouraging though these results may seem, the researchers still have a long way to go. Scientists will need to work out the right cocktail of drugs in order to achieve both “shock” and “kill” without toxic side effects. Still, it’s encouraging that the promising agent is already FDA-approved, which could shorten the length of trials should further cell and animal studies yield similarly positive results.