New HIV Strategy Aims to ‘Shock and Kill’ Dormant Virus

Antiretroviral drugs allow HIV-positive people to lead full and healthy lives, but a cure requires killing so-called latent HIV cells in the body.

Antiretroviral drugs allow millions of people to live healthy and full lives with human immunodeficiency virus (HIV), but they aren’t a true cure. While daily antiretroviral therapy can effectively halt the spread of the HIV, the virus is never fully eradicated. HIV is able to hide out in the body’s own immune cells in a dormant state, untouched by conventional treatments. If a patient stops taking the drugs for any reason, the sleeping virus is likely to reactivate and spread.

Flushing out dormant HIV is one of the last barriers to a cure and researchers worldwide are chasing down solutions to so-called HIV latency. Now a team from California believes it’s discovered a way to reactivate latent HIV and draw it out from hiding. It’s the first step in a larger “shock and kill” strategy that could ultimately free individuals with HIV from a lifetime of antiretroviral therapy.

In a paper published in Cell Host & Microbe, scientists from the Gladstone Institutes described how a naturally occurring enzyme in the body called SMYD2 plays a key role in keeping the latent HIV virus asleep. By targeting this enzyme with special molecules originally developed for cancer therapy, the Gladstone team was able to inhibit SMYD2 and rouse the dormant HIV.

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Melanie Ott, a senior investigator at the Gladstone Institute for Virology and Immunology, and professor of medicine at the University of California, San Francisco, said that the experimental treatment reactivated only a fraction of the dormant HIV virus in cells donated by HIV patients, but that it’s a solid step forward.

“We don’t want to raise false hopes,” said Ott. “We don’t have the pill to cure HIV, but for us it provides an important piece of the puzzle.”

Latent HIV is so hard to eradicate because it hides in the body’s own T cells, specifically the “memory” T cells. Those are the long-living immune cells that “remember” vaccines and other immune system events so that the body can fight off a repeat attack. The dormant HIV “pools” in these T cells and therefore stays under the radar of antiretroviral drugs.

“The idea is to artificially reawaken the virus to get rid of these dormant cells embedded in the immune system,” Ott said.

To do that, scientists needed to better understand how and why latent HIV goes into a deep sleep. When the HIV virus invades a healthy cell, it slips its own viral DNA into the cell’s nucleus. Rather than being a long strand of DNA, the viral DNA wraps tightly around proteins called histones in what looks like a chain of pearls.

“If the DNA is more tightly wrapped around the histones, it’s in a suppressed state. If it’s less tightly wrapped, it’s more active,” Ott explained. The SMYD2 enzyme plays an important role because it modifies a “very specific site on a specific histone” that keeps the viral DNA tightly wrapped, stopping the virus from activating and spreading. “But if you can inhibit the expression of SMYD2, it will loosen the hold.”

That’s where AstraZeneca comes in. The drugmaker had already been experimenting with SYMD2 inhibitors for use in anti-cancer drugs, but had hit a wall. AstraZeneca lent Ott’s lab some of the molecules it had developed to target SMYD2, with hopefully better results against HIV.

Ott’s team tested the molecules on human T cells donated from HIV patients actively undergoing antiretroviral therapy and the early results were promising, but not complete. For the “shock and kill” strategy to work, 100 percent of latent cells have to be reactivated. Otherwise, the virus could always come back.

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Critics of the “shock and kill” strategy doubt if we’ll ever be able to completely flush out all latent HIV. An alternative approach is to forget about waking up dormant HIV altogether and instead lull the latent virus into a permanent deep sleep. Ott wonders if that could be done without replacing antiretroviral therapy with another lifelong treatment regimen.

Then again, said Ott, maybe there’s a third way, a combination of “shock and kill” and the silencing technique.

“Some cells are much more easily reawakened, and others are much more dormant and in a state of deep latency,” said Ott. “Maybe we can apply ‘shock and kill’ therapy initially to get the easily reactivated cells. Then we can apply a second wave of treatment to send the cells that aren’t responding into an even deeper state of latency.”

What’s clear is that more research collaborations are required to complete the puzzle of a permanent, drug-free cure for HIV. Ott emphasizes that even her team’s SMYD2 success is only half of the “shock and kill” strategy. Once the latent HIV is shocked awake, we still need powerful new weapons to take it out for good.

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