A small molecule currently in clinical trials for treating cancer can suppress HIV-1 in mice, a new study shows (Proc. Natl. Acad. Sci. USA 2015, DOI: 10.1073/pnas.1511144112). The compound, known as INK128, likely works against both cancer and HIV-1 because of its mode of action: It inhibits a protein, mTOR, which regulates the transcription of genes.
Researchers at the University of Maryland School of Medicine who carried out the study believe that, in the case of HIV, INK128 acts in part by blocking the transcription of a surface receptor, CCR5, which the virus latches onto to enter immune cells. They think that INK128 also prevents the transcription of HIV genes after the virus inserts them into the immune cells, making it the first compound to deter HIV in this way.
The Maryland team engineered mice to produce human immune cells and infected the animals with HIV. When exposed to INK128, these mice had lower virus counts and improved immune cell concentrations. “These findings indicate that mTOR inhibitors warrant Phase II proof-of-concept trials,” says pathologist Ferdinando Nicoletti of Italy’s University of Catania, who was not involved with the study.
Older HIV drugs inhibit proteins carried by the virus itself, but new approaches like this one target proteins that belong to an infected immune cell. “We were running out of targets” in HIV to aim drugs at, says Robert C. Gallo, an author on the new study.
Cellular drug targets such as mTOR are attractive to researchers because they mutate less frequently than do viral proteins. Fewer mutations mean a lower likelihood of drug resistance. “Patients with drug-resistant HIV are difficult to treat,” says Alonso Heredia, also a member of the Maryland team. “For these patients, [mTOR inhibitors] could help.”
Because INK128 and other mTOR inhibitors are being used or investigated as cancer drugs, the new agent may also benefit patients with both HIV and cancer. These two illnesses are difficult to treat together, because of drug interactions, but they often occur together for reasons still being explored.