Searching for a Functional Cure for HIVR&DMag
by Lindsay Hock
August 3, 2015

In 2014, more than 1.2 million people in the U.S. were noted by the Centers for Disease Control and Prevention (CDC) as living with HIV infection. Almost one in eight, or 12.8%, are unaware of their infection. The CDC estimates that 1,218,400 person aged 13 and older are living with HIV infection, including 156,300 who are unaware of their infection. Over the past decade, the number of people living with HIV has increased, while the annual number for new HIV infections has remained stable.

For those HIV-infected patients that are aware of their illness, antiretroviral therapy (ART) is available to suppress the virus. These patients will remain on ART for life, because the virus survives over the long-term in infected dormant cells. Interruption of current ART results in a rebound of the virus and clinical progression to AIDS.

So far, approximately 26 drugs are available as ART. These drugs include compounds that block the entry of the virus, reverse transcription, integration and maturation of the virus. There are still many unknowns in HIV research, but what researchers do know is that used in combination, ART cocktails can reduce the viral plasma load of an infected individual to below the level of detection. “The current drugs have transformed HIV disease more into a chronic disease rather than a death sentence,” says Susana Valente, associate professor at the Scripps Research Institute in an exclusive interview with R&D Magazine. “They have truly been amazing to reducing the replication of the virus.”

The difficulty behind HIV vaccines and drugs
While there are many ART options approved by the U.S. Food and Drug Administration (FDA), drugs to cure HIV and vaccines have failed in previous trials, such as the Thai trial. The reason for this: the HIV virus mutates and evolves at a fast pace.

The difficulty of developing a vaccine for HIV is based on the envelope of the virus. The envelope of the virus changes fast and is covered in carbohydrates and it hides itself from broadly neutralizing antibodies. “Essentially, the virus evolves in a way to keep away from neutralization,” says Valente. “And, although there are some broadly neutralizing antibodies that do block the virus, therapies taking advantage of these are still in the works.”

In terms of drug development, much work focuses on the suppression of the virus. Although current drugs suppress the virus, the virus is still integrated into the host genome. “Once it’s there, it’s hard to eliminate the virus,” says Valente. “Besides, another feature of this virus is that it goes into a state of dormancy or latency.” If the virus isn’t showing signs of itself, it’s hard to find strategies to eliminate it.

A new hope
HIV latency is a global issue, but now there’s new hope to reduce the HIV reactivation rate due to latency. Scientists from the Florida campus of the Scripps Research Institute (TSRI) have shown that, unlike other ART therapies, a natural compound called Cortistatin A reduces residual levels of virus from infected dormant cells, establishing a near-permanent state of latency and greatly diminishing the virus’ capacity for reactivation.

“Cortistatin A is a natural product isolated from a marine sponge found in Southeast Asia,” says Valente. Initially there was interest in this molecule because it has anti-angiogenic properties, and this triggered the development by several synthetic chemists of the product via a synthetic route because there wasn’t a lot of it available in nature. “So, we are working with an analog of the natural product which is called didehydro-Cortistatin A (dCA), which is similar in structure and has the same activity,” says Valente.

dCA inhibits Tat, an important protein in the lifecycle of the HIV virus that is responsible for viral amplification and replication. “If you don’t have Tat, the virus is much weaker and it can’t sustain a productive infection for long,” says Valente.

In TSRI’s research, dCA has shown to inhibit replication in HIV-infected cells by significantly reducing levels of viral messenger RNA—the blueprints for producing proteins and more infection. In fact, in latently infected primary T cells isolated from HIV subjects treated with ART drugs, dCA reduced viral reactivation by 92.3%. These results suggest an alternative to the “shock and kill” strategy, a widely studied strategy for eradication of latent HIV, which tries to purge viral reservoirs by shocking them out of their latency with reversing agents, while stopping new rounds of infection with ART. The expectation is that infected cells will die from excessive viral replication or be killed by the immune system effects, explains Valente.

“Our approach is the exact opposite of the ‘shock and kill’ strategy,” says Valente. “We are suppressing the cell that’s infected to such low levels that there’s no viral production and no events of re-expression. And, basically with time, we are expecting there will be turnover of these infected cells; and with time, without replenishing the system, we will reduce the size of the reservoir.” Essentially, it’s putting the virus to sleep instead of reactivation.

There are currently no other drugs in the pipeline or on the market that target the Tat protein.

Clinical studies
TSRI researchers are currently doing tests in humanized mice. They will be starting testing in non-human primates next year.

“We are in the process of using the available animal models to test this idea of suppressing the reservoir with our Tat inhibitor to assess long-term results of reducing the reactivation of the virus,” says Valente.

The team still must research the molecular mechanisms behind the non-reactivation of the virus in the presence of dCA. And they must also understand how the drug can be used in patients. Should it be added to ART treatment or used alone after the virus has been dramatically suppressed? The results so far seem promising. The researchers hypothesize that if taken in conjunction with ART drugs, patients may be able to take a break from the costly medication with multiple side effects for a period of time without immediate viral rebound.

“Another interesting tidbit is Tat is also responsible for neurotoxic activities in the brain,” says Valente. About 50% of HIV-infected individuals will experience some neuro-impairment. Most of these cases are mild, yet effects can range up to dementia.

“We have initiated studies on the activity of this compound in reducing neurotoxicity, and the results seem promising” says Valente. So, the drug compound has several benefits for HIV-infected individuals.

This is just one more step to eradicating the virus, should the compound pass all clinical studies and regulations set by the FDA.