Waking up HIV: Two compounds show great potential to rouse latent virus

July 30, 2015, UC Davis
HIV, the AIDS virus (yellow), infecting a human immune cell. Credit: Seth Pincus, Elizabeth Fischer and Austin Athman, National Institute of Allergy and Infectious Diseases, National Institutes of Health.

Highly active anti-retroviral therapy (HAART) has helped millions survive the human immunodeficiency virus (HIV). Unfortunately, HIV has a built-in survival mechanism, creating reservoirs of latent, inactive virus that are invisible to both HAART and the immune system.

But now, researchers at UC Davis have identified a compound that activates latent HIV, offering the tantalizing possibility that the virus can be flushed out of the silent reservoirs and fully cured. Even better, the compound (PEP005) is already approved by the FDA. The study was published in the journal PLOS Pathogens.

"We are excited to have identified an outstanding candidate for HIV reactivation and eradication that is already approved and is being used in patients," said lead author Satya Dandekar, who chairs the Department of Medical Microbiology and Immunology. "This molecule has great potential to advance into translational and clinical studies."

While HAART has been quite successful - reducing HIV infection in newborns, restoring patients' immune systems and lowering viral loads to virtually undetectable levels - these therapies cannot cure the disease alone. Once treatment is discontinued, pools of latent virus reactivate, and the infection comes roaring back. As a result, patients must remain on treatment indefinitely, posing the risk of long-term toxicity.

"We've made great progress, but at the end of the day you still have more than 30 million people walking around with HIV," said Dandekar. "Without drugs, the virus can come back at the same threat level for patients. Eradicating HIV is extremely critical."

Eradication means activating latent virus and destroying it, a strategy called "shock and kill." Researchers around the world have been working on this approach, but finding the right compounds has been challenging. A successful molecule must precisely target proteins associated with HIV latency without overstimulating the or wantonly activating protein master switches, such as NF-kappaB. Either outcome can generate severe side effects.

The UC Davis team may have succeeded with PEP005, the active ingredient in the FDA-approved anti-cancer drug PICATO, which increased HIV activation in patient blood samples and showed low toxicity.

However, HIV is a complicated virus and, as clinicians have discovered with HAART, must be treated through multiple means. In addition to PEP005, the researchers tested other compounds capable of reactivating HIV through different pathways. This painstaking process identified another molecule, JQ1, which works synergistically with PEP005 to maximize HIV activation. PEP005 when combined with JQ1 increased HIV activation up to 15-fold.

While these results are promising, researchers are mindful that "shock" only works when it's followed by "kill."

"First, we need to identify the best combination of latency-activating agents," said Dandekar. "Then we must help patients clear these reactivated cells. Just reactivating the HIV from latency won't be enough."

Dandekar notes that many HIV patients receiving HAART regimens have robust immune responses, which will go a long way towards clearing the virus. She also believes HIV vaccines in development could give patients an extra edge. Even a vaccine that isn't 100 percent effective at preventing transmission could boost a patient's ability to destroy reactivated .

However, identifying PEP005 and JQ1 as potent HIV-activators is a key step in the right direction.

"It is really exciting is that the molecule in PICATO is already approved and being used by ," said Dandekar. "In addition to being very effective in reactivating HIV, it also works beautifully with other latency reactivating agents, is less cytotoxic and doesn't cause a major immune response."

Explore further: New model to study HIV latency in brain cells

Related Stories

New model to study HIV latency in brain cells

June 18, 2015
Over 35 million people worldwide are currently infected by HIV. Antiviral therapies can keep the virus from multiplying. However, no drug can cure infection so far, because various cell types continue to carry the virus in ...

Identification of drug combinations that reverse HIV-1 latency

March 30, 2015
There are almost 40 million people throughout the world living with HIV-1/AIDs. While current antiretroviral therapies are able to reduce the amount of virus in the blood, HIV remains present in a latent state within T cells. ...

Designed drug candidate significantly reduces HIV reactivation rate

July 8, 2015
HIV-infected patients remain on antiretroviral therapy for life because the virus survives over the long-term in infected dormant cells. Interruption of current types of antiretroviral therapy results in a rebound of the ...

Cancer drug shows promise in eradicating latent HIV infection

November 29, 2012
Breakthrough drugs have made it possible for people to live with HIV longer than ever before, but more work must be done to actually cure the disease. One of the challenges researchers face involves fully eradicating the ...

Improving the effect of HIV drugs by the use of a vaccine

April 28, 2015
A vaccine containing a protein necessary for virus replication can boost an HIV-infected patient's immune system, according to clinical research published in the open access journal Retrovirology. This boost can result in ...

Drugs fail to reawaken dormant HIV infection

March 23, 2014
Scientists at Johns Hopkins report that compounds they hoped would "wake up" dormant reservoirs of HIV inside immune system T cells—a strategy designed to reverse latency and make the cells vulnerable to destruction—have ...

Recommended for you

Researchers find new way to defeat HIV latency

March 8, 2018
HIV, the virus that causes AIDS, has a secret life. Though anti-retroviral therapy can reduce its numbers, the virus can hide and avoid both treatments and the body's immune response.

Broadly neutralizing antibody treatment may target viral reservoir in monkeys

March 5, 2018
After receiving a course of antiretroviral therapy for their HIV-like infection, approximately half of a group of monkeys infused with a broadly neutralizing antibody to HIV combined with an immune stimulatory compound suppressed ...

HIV begins to yield secrets of how it hides in cells

March 2, 2018
UC San Francisco scientists have uncovered new mechanisms by which HIV hides in infected cells, resting in a latent state that evades the body's immune system and prevents antiviral drugs from flushing it out.

HIV exports viral protein in cellular packages

February 15, 2018
HIV may be able to affect cells it can't directly infect by packaging a key protein within the host's cellular mail and sending it out into the body, according to a new study out of a University of North Carolina Lineberger ...

Can gene therapy be harnessed to fight the AIDS virus?

February 13, 2018
For more than a decade, the strongest AIDS drugs could not fully control Matt Chappell's HIV infection. Now his body controls it by itself, and researchers are trying to perfect the gene editing that made this possible.

Big data methods applied to the fitness landscape of the HIV envelope protein

February 7, 2018
Despite significant advances in medicine, there is still no effective vaccine for the human immunodeficiency virus (HIV), although recent hope has emerged through the discovery of antibodies capable of neutralizing diverse ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.