New drugs reawaken latent HIV to eradicate virus

A new study suggests a class of drugs already being tested in clinical trials for the treatment of cancer may also hold the key to complete eradication of HIV.

In the journal Cell Host & Microbe, a team led by researchers from the Sanford Burnham Prebys Medical Discovery Institute (SBP) in La Jolla, CA, reveals how drugs called Smac mimetics suppress dormant HIV (human immunodeficiency virus) cells among patients treated with antiretroviral therapy (ART).

ART is a combination of at least three antiretroviral drugs that slows the progression of HIV. While the treatment has led to significant reductions in death rates from HIV around the globe, the search continues for a way to eliminate the disease once and for all.

Antiretroviral drugs work by preventing HIV cells from multiplying, reducing levels of the virus in the body and giving the immune system the opportunity to stave off other infections.

However, HIV is never completely eradicated in patients treated with ART; the virus can lay dormant in cells, escaping detection by the immune system.

“If you take people off their antiretroviral therapies, some of these dormant cells reawaken to make more virus and re-establish disease,” explains lead study author Lars Pache, PhD.

“The key for a cure for HIV is to purge these cells that have dormant HIV.”

This type of strategy is referred to as a “shock-and-kill” approach, but although it is a method that has been widely investigated by researchers in recent years, it has yet to see success.

Pache and colleagues explain this is because candidate drugs used to reawaken dormant HIV – such as latency reversing agents (LRAs) – are not potent enough or can trigger immune system overactivity, which can be deadly.

A ‘one-two punch’ for HIV

After searching for genes within host cells that aid in the suppression of HIV, the team identified one gene – called BIRC2 – that when absent, increases HIV activity.

Because Smac mimetics work by blocking BIRC2 and molecules related to the gene, they investigated whether the drugs could reawaken dormant HIV, allowing it to be identified and attacked by the immune system.

The team notes that one of the reasons why HIV can hide from the immune system is because it is covered by “tightly wound” DNA.

They hypothesized Smac mimetics may work well with another class of drugs called histone deacetylase inhibitors, which can unwind this DNA, revealing the HIV underneath.

The researchers tested a Smac mimetic called SBI-0637142 combined with a histone deacetylase inhibitor called panobinostat on cells from HIV-infected patients undergoing ART.

They found that the drug combination reawakened HIV in the cells without activating the immune system.

They also tested another Smac mimetic called LCL161 – currently being tested in phase 1 and 2 clinical trials for the treatment of cancer – combined with panobinostat, finding that the treatment produced similar results.

Based on their findings, the team suggest Smac mimetics – in combination with other drugs such as histone deacetylase inhibitors – could be potential candidates for an HIV cure.

Study co-author Sumit Chanda, PhD, adds: “This is a one-two punch for HIV.

Our internal drug possesses about 10-100 times more potent LRA activity than the small molecules currently in clinical development, making it a promising next-generation candidate to tackle HIV latency.”

The researchers say they now hope to team up with a pharmaceutical company in order to develop Smac mimetics for assessment in clinical models of HIV latency, before moving to human trials if they are deemed safe and effective.

Because the drugs are already being tested in clinical trials, the team says the approval process for their use in the treatment of HIV is likely to be shorter.

In July, Medical News Today reported on a study published in PLOS Pathogens in which researchers found HIV cells awaken much less frequently than previously thought following ART.

While latent HIV cells were believed to awaken around four to five times a day once ART had ceased, the new study found they actually only awaken once a week. – Medical News Today

November 2015
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