The highly active antiretroviral therapy (HAART) has helped millions survive the human immunodeficiency virus (HIV). Unfortunately, HIV has a survival mechanism, create reservoirs where it is dormant, inactive viruses that are invisible to the HAART therapy and the immune system.
But now, researchers at UC Davis have identified a compound that activates the latent HIV, offering exciting possibility that the virus could be taken out of the silence of their reservoirs and the infection can, in this case turn out to be completely healed. Or, better yet, the compound (PEP005) has been approved by the FDA. The study was published in the journalPLoS Pathogens.
"We are excited to have identified an excellent candidate for reactivating the eradication of HIV that has already been approved and is being used in patients," said authorSatya 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, the restoration of the immune systems of patients and reducing viral loads to virtually undetectable levels, these therapies can not cure the disease alone. Once the treatment is stopped, the reservoirs of latent virus is reactivated and back to renewed infection. As a result, the patient should be treated indefinitely with long-term toxicity risk.
"We have made great progress, but at the end of the day you still have more than 30 million people walking around with HIV," said Dandekar. "No drugs, the virus may return to the same level of threat to patients. Eradicate HIV is extremely critical. "
Eradication means activate latent virus and destroy it, a strategy called the "kick and kill." Researchers around the world have been working on this approach, but finding the appropriate compounds was challenging. The great thing is to create a molecule that must precisely reach and activate proteins associated with HIV latency without over stimulating the immune system or is obscured by activating protein master, as NF-kappaB. The result could generate 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 viruses such as found with medical HAART, and should be treated through various means. Besides PEP005, the researchers tested other compounds able to reactivate HIV through different paths. This thorough process has identified another molecule, JQ1, working synergistically with PEP005 "to maximize ativaçãodo HIV. The PEP005 "when combined with JQ1 causes HIV activation to 15 times'.
"A single treatment is not enough, which is why we are trying to achieve HIV through two different routes," said first author Guochun Jiang. "As a result, we may see more dramatic viral activation."
Although these results are promising, researchers are aware that the "kick" only works when it is followed by "killing".
"First, we need to identify the best combination of activating agents of HIV in a state of latency," Dandekar said. "So we need to help patients to destroy and erase those cells with HIV reactivated. The simple reactivation of latent HIV will not be good enough. "
Dandekar notes that many patients with HIV receiving HAART regimens provoke a strong immune response, and that there is a long way to eliminate the virus. It also believe that vaccines in development could provide an additional benefit to patients. Even if a vaccine is not 100 percent effective at preventing transmission, it may 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. "Besides 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 included authors like 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).