Can a Cancer-Fighting Drug Hunt Down Dormant HIV?

HIV has a remarkable ability to hide out in parts of the body that are out of reach of antiretrovirals. In these HIV reservoirs or "sanctuaries," viral reproduction can continue even after antiretroviral therapy has successfully decreased production of the virus in other parts of the body.

As Plus reported earlier this year, luring HIV out of these reservoirs is essential for any cure or vaccine. Reservoirs have been previously found in the lymphatic system and a new study published in Oxford Journals, reports scientists have found HIV sancturaries can in the central nervous system, eye retinas, male testes, the urinary tract, and other tissues and organs. 

The reason why sanctuaries are a problem is because HIV hide out there, appearing dormant but slowly replicating itself  —   in a state that some might call "latency" or "remission" — then suddenly ramp up the viral reproduction. 

Addressing this hurdle has been an ongoing problem facing scientists, but new research suggests a solution. At the 28th International Conference on Antiviral Research (ICAR), Arno Therapeutics, a biotech company in New Jersey which has primarily focused on cancer-fighting drugs reported one new treatment could fight HIV, too. The medication known as AR-12, seems to have broad antiviral potential, capable of fighting a variety of viruses including influenza, Ebola, the Marburg virus ans HIV. 

AR-12 works in a way completely different from anti-HIV drugs currently in use. Although it is very early in development, the drug appears to achieve its antiviral effect by influencing so-called "chaperone proteins." 

Chaperone proteins fold, refold, and discard terminally-misfolded proteins within cells. They latch on to misfolded proteins and escort them to be refolded, or if the proteins are unable to be used again, they carry them off to be destroyed. 

It may sound like a paper-folding game you played as a child, but the science is sound, and serious. This protein-folding process also occurs during viral replication, where large amounts of viral proteins are produced. Certain viruses like HIV not only generate their own chaperone proteins, but also hijack those of the cells it infects.

HIV forces these hijacked chaperone proteins to help in its course of infection by alleviating stress within the cell during infection, allowing for the viral replication process to continue. In other words, hijacked chaperone proteins are vital to how HIV successfully replicates itself. 

One special type of chaperone proteins are called heat shock proteins and AR-12 serves as an external variable "downregulating" these proteins by making the cell slow production of the heat shock protein. Without enough heat shock proteins available to be used and hijacked by HIV, the viral proteins are  unable to be properly folded, and the misfolded proteins are unable to be cleared, forcing the cell into apoptosis (a type of cell suicide that plays a significant role in HIV infections). Simply put, AR-12 halts production of a vital element in HIV's replication process. 

AR-12 appears to do even more than that. Researchers found that the drug also helps with a process called "cell autophagy." Cell autophagy is the process by which unneeded pieces of the cell (or infectious agent) are removed or recycled. Without this process, the cell would become overloaded with cellular debris and would self-destruct.

Research shows that host-cell autophagy plays an important role in HIV replication. For certain viruses like HIV, avoiding autophagy is critical for replication. 

Here's how AR-12 may be able to help the HIV sancturary problem. In the preclinical development phase, AR-12 has shown that it can rapidly get from the blood stream into tissues where the viral infection is ongoing, including the brain, kidney, and liver. The penetration of AR-12 into the tissues where the viral infection is active is an important aspect of the drug's ability to control the viral infection. 

A separate study conducted by researchers at University College London's Wohl Virion Centre and the Medical Research Council Centre for Medical Molecular Virology, Division of Infection and Immunity, found that inhibiting heat shock proteints would keep latent HIV in sanctuary regions from being reactivated. Inhibiting heat shock proteins is something that AR-12 appears to do realtively well.

"The research uncovered an important target that controls HIV-1 reactivation from its dormant state in the cells. "  Dr. Ariberto Fassati, Director The Wohl Virion Centre reported, “We are proposing an approach to keep the virus dormant, and hopefully obtain lasting remissions. After all, the so-called latency is a problem only because the virus sooner or later becomes active again." 

AR-12 has previously been studied in a phase 1 clinical trial for patients with cancer. Given at relatively high doses to patients for up to 33 weeks, the drug was well tolerated. 

This research is important because it could open up an entirely new means of fighting the virus in both active and dormant cells. AR-12's potential could help establish an entirely new class of HIV treatment. Drugs that target the chaperone proteins that AR-12 effects could dramatically halt HIV replication, and move researchers one step closer to a cure.