Lurking beneath the surface, HIV is always ready to wage war. Much like our stealthiest submarines, the virus has developed a built-in survival mechanism, giving it the power to hide from current drugs as well as from our immune system.
When HIV infects an individual, it harnesses the immune system machinery to replicate itself and create an army of HIV particles. Current drugs keep HIV patients alive by stopping this reproduction process, but HIV has a secret weapon: It can go silent and evade the detection of the tools scientists have developed to fight the disease.
Researchers at UC Davis recently found a combination of two molecules that together have the potential to seek out and destroy the hidden virus, completely eliminating the disease from those infected. With an estimated 36.9 million people worldwide living with HIV in 2014, the therapeutic advance promises a global impact.
“We don’t have any really good tool to kill the virus,” said Guochun Jiang, the first author of the paper that describes the work. “This is the problem and this is a very important public interest.”
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As a bonus, researchers may have found the tool in a cancer drug that’s already been approved by the U.S. Food and Drug Administration. Prior approval means the treatment could bypass years of regulatory obstacles for clinical trials, accelerating its way to patients.
“When any new compounds get discovered or identified, it takes a really, really long time for them to go through patient clinical trials,” said Satya Dandekar, lead author of the paper and professor of microbiology at UC Davis. “It takes an enormous amount of resources and the major limitation is really the amount of time it takes.”
For that reason, she said, her lab “took a different approach.”
She added that the group asked themselves, “What are the molecules or compounds which already have great promise and have already been in use in patients, so at least we know they are safe to use in humans?”
People who are HIV positive take a regimen of drugs to combat infection, defend the immune system and provide protection from drug resistance. With five different classes of HIV medication, people generally take three drugs from at least two classes.
Patients take more than one drug because doctors want to attack the virus at all possible angles of the replication process to give those infected the best chance at survival. The ability of HIV to survive the onslaught of medication comes down to its ability to clock itself and become invisible.
“HIV has the ability to go into a latent, silent state in the cells,” Dandekar said. “This is a tremendous capacity of the virus in that it can manipulate, exploit and hijack the host immune surveillance and controlling mechanisms and use it for its own benefit. While there is the whole storm of the viral infection, right in that storm is the calmness that the virus sits in. The immune system cannot detect it. They pose a major threat and danger.”
The virus cannot cause harm in these hiding spots, but it is always waiting to attack if a person stops undergoing therapy. Even our most effective HIV drugs, if taken for 50 years or more, can’t reach the virus in this silent state.
One emerging method to get rid of the virus is called “shock and kill,” a two-part process that involves “shocking” hidden virus particles out of concealment. While it causes the unmasked virus to start replicating, it also means that HIV is now detectable, and can be “killed” by drugs and the immune system.
An ideal drug therapy would need to do both processes, and new research from Dandekar’s lab recently demonstrated the power of a compound, known as PEP005, in a current cancer drug for “shocking” the virus. Molecules like these could eventually be incorporated into current therapies to completely eliminate the virus from infected individuals.
PEP005 was able to revive HIV from its silent form into an active virus. It’s contained in a drug called PICATO, which is FDA-approved for treatment of actinic keratoses, or skin lesions that can to turn into skin cancer. The compound proved successful in test tubes and cell samples taken from patients with HIV.
Researchers tested PEP005 in combination with other chemicals, and found that a molecule known as JQ1 works synergistically with it. These two compounds together increased HIV activation from its silent state by 15-fold compared with instances where no drugs were administered.
These two compounds will continue to be studied in the lab, but the process of getting effective medication into infected humans could be expedited since one of them is already FDA-approved.
“At the end of the day, we are really talking about lots of HIV-infected patients out there,” Dandekar said. “The focus is really them and HIV eradication. HIV has been a major cost on very precious human life and the quality of life.”
This work was published online in PLOS Pathogens on July 30. Researchers from the University of California, San Francisco, the San Francisco Veterans Affairs Medical Center and Williams College collaborated on this study.