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Shock & kill: Battle plans for attacking HIV and other updates from the 2016 HIV Cure Summit [part 2]

, by Emily Land

Many people believe a “shock and kill” strategy will be part of a future HIV cure. With this strategy, CD4 cells that are latently infected with HIV are “shocked” into producing virus, and then targeted for destruction by the body’s immune system.

Warner Greene, MD, PhD

Warner Greene, MD, PhD

At the amfAR HIV Cure Summit at UCSF held on World AIDS Day, Warner Greene, MD, PhD, delivered news about an exciting advance in shock and kill research. He shared findings about a drug approved for the treatment of psoriasis, called acitretin, that can selectively activate and kill CD4 cells latently infected with HIV.

Putting the “kill” in “shock and kill”

“It’s a fascinating type of model,” said Greene, as he described a series of studies conducted on acitretin by Dr. Peillin Li and Dr. Joe Wong. Acitretin, reported Greene, takes advantage of a biological defense system called “RIG-I.”

“Acitretin can induce new expression of RIG-I—it can wake the virus up out of slumber,” explained Greene. “If viral RNA is being expressed, it can bind to the RIG-I, and activate a cell death pathway that causes that cell to selectively die,” he said.

This capability—to both re-activate latent cells and cause their death—hasn’t yet been shown with other latency-reversing agents yet.

Acitretin reduces the concentration of HIV DNA in cell cultures (Slide: Warner Greene

Acitretin reduces the concentration of HIV DNA in cell cultures (Slide: Warner Greene)

This agent has not been tested in studies with humans or animals yet, however. Greene reported that a clinical trial proposal is now underway to test acitretin as a way to selectively kill HIV reservoir cells that are producing virus.



Research on “shocking” agents

Dr. Greene also shared research on other shocking agents called “toll-like receptor” (TLR) agonists.

Read previous TLR-7 agonist HIV cure research on BETA.

Green’s team investigated how TLR-7 agonists, which bind to proteins called “toll-like receptors” on the surface of CD4 cells, activate CD4 cells. In a study where his team treated latently-infected CD4 cells with TLR agonists, latently infected CD4 cells produced a moderate amount of virus in the presence of dendritic cells but not in isolation. This showed that the action of TLR agonists isn’t direct—it’s mediated through dendritic cells (which are a different cell of the immune system).

With TLR-7/8 and TLR-4 agonists, there was about a 3-fold increase in virus production. “This is a response, but it’s not a great response,” said Greene. “We didn’t hit it out of the park with this study.”

In a subsequent study, Greene shared that they tested TLR agonists using “gold standard” cells—or ones actually taken from a person living with HIV on long-term antiretroviral therapy (as opposed to cells infected with HIV in the lab).

There was a 12-fold response in virus production to TLR-4, and modest responses to the TLR-7, TLR-8, TLR-7/8, and TLR-9 agonists.

“These agents appeared to be more active when they’re given in vivo—in animal models or humans,” he said.

Moving forward, his team will continue research on harnessing the innate immune response to kill cells that are part of the latent HIV reservoir.

Read additional HIV cure research later this week on BETA.



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