(SACRAMENTO, California) -
Highly effective antiretroviral therapy (HAART) has helped millions survive the human immunodeficiency virus (HIV). Unfortunately, HIV has a survival mechanism, creating reservoirs where it is latent, inactive viruses that are invisible to HAART Therapy and the immune system.
But now researchers at UC Davis have identified a compound that activates latent HIV, offering an exciting possibility that the virus can be taken out of the silence of its reservoirs and the infection can in this case be completely cured. Or, better yet, the compound (PEP005) has already been approved by the FDA. The study was published in the journal PLoS Pathogens.
"We are excited to have identified an excellent candidate for reactivation of HIV eradication that has already been approved and is being used in patients," said the author Satya Dandekar, Who chairs the Department of Medical Microbiology and Immunology. "This molecule has great potential to advance translational research and clinical studies."
While HAART has been very successful in reducing HIV infection in newborns, in restoring patients' immune systems, and reducing viral loads to virtually undetectable levels, such therapies can not cure the disease alone. Once the treatment is stopped, the reservoirs of the latent virus reactivate, and the infection recurs again. As a result, the patient should be treated indefinitely, with a long-term risk of toxicity.
"We have made great strides, but at the end of the day you still have more than 30 millions of people walking around with HIV," Dandekar said. "Without drugs, the virus can return to the same level of threat to patients. Eradicating HIV is extremely critical. "
Eradication means activating latent virus and destroying it, a strategy called "kicking and killing." Researchers around the world have been working on this approach, but finding the right compounds was challenging. The big balcony is to create the molecule that must precisely reach and activate the proteins associated with HIV latency without super stimulating the immune system or that is clouded by the master activator protein, such as NF-kappaB. The result could lead to serious side effects.
The UC Davis team may have achieved with PEP005, the active ingredient in FDA approval to Picato anti-cancer drug, which increased the activation of HIV in patient blood samples and showed low toxicity.
Three-dimensional structure of cell releasing surface with HIV particles through the plasma membrane of the host (courtesy of Laboratory Cheng Holland, PA © Regents).
However, HIV is a complicated virus, as doctors have discovered with HAART, and should be treated through various means. In addition to PEP005, the researchers tested other compounds capable of reactivating HIV through different pathways. This meticulous process has identified another molecule, JQ1, that works synergistically with PEP005 "to maximize HIV activation. The PEP005 "when combined with JQ1 causes HIV activation up to 15 times greater."
"A single treatment is not enough, which is why we are trying to reach HIV through two different pathways," said first author Guochun Jiang. "As a result, we can see more dramatic viral activation."
Although these results are promising, the researchers are aware that the "kick" only works when it is followed by "kill."
"First, we need to identify the best combination of HIV-activating agents in a state of latency," Dandekar said. "So we have to help patients destroy and erase those cells with reactivated HIV. The simple reactivation of latent HIV will not be good enough. "
Dandekar notes that many HIV patients receiving HAART on dosing schedules provoke a robust immune response, and that there is a long way to eliminate the virus. She also believes that developing vaccines could give patients an added advantage. Even though a vaccine that is not 100 effective percent in preventing transmission, it can increase the patient's ability to destroy the virus reactivated.
However, PEP005 and JQ1 identified as potent activators of latent HIV is a key step in the right direction.
"It's really exciting is that the molecule in PICATO is already approved and is being used by patients," Dandekar said. "In addition to being very effective in reactivating HIV, it also works beautifully with other agents capable of activating the latent virus and is less cytotoxic, not causing a major immune response."
There are other authors included, such as Erica A. Mendes, Yuyang Tang, Anne Fenton, Gregory P. Melcher, James EK Hildreth, George R. Thompson at UC Davis, Philipp Kaiser and Joseph K. Wong at UC San Francisco; and Daniel P. Wong at Williams College.
This work was funded by NIH grants DK61297, AI43274; UC Davis Research Investments in Science and Engineering (RISE) grant; a postdoctoral fellowship from CAPES / Brazil (BEX 2951 / 12-6); and a grant from the Swiss National Science Foundation (PBZHP3_147260).