One of the biggest challenges facing doctors who treat AIDS patients has been HIV's ability to hide in the body. Even though a barrage of powerful anti-retroviral drugs can virtually eliminate HIV to the point of being undetectable in the bloodstream, the virus still has the ability to hide out in the body for years. HIV continues to multiply during this time, a clever scheme to ensure its survival, which is why curing AIDS has been illusive.

But researchers at the UR have discovered that an existing drug, miltefosine, which has been used in Germany for the treatment of breast cancer and in the US for parasite infection, can also deny HIV its safe havens.

Infection from the Human Immunodeficiency Virus (HIV) is believed to be the primary cause of Acquired Immune Deficiency Syndrome (AIDS). Even though considerable advances have been made over the last 20 years, more than 40 million people are infected with HIV worldwide, and about 3 million people die from AIDS each year. As of 2006, there were 3,025 reported AIDS cases in Rochester, and a steady 40,000 new cases of HIV infection are reported in the US annually.

While drug combinations, sometimes called "cocktails," have been able to extend the lives of people living with AIDS, many people cannot tolerate them. And conditions like AIDS-related dementia greatly reduce the quality of life for people who do live longer. Eventually the virus's ability to hide in the body, and replicate itself, allows it to overcome the immune system.

Researchers have long understood that HIV has the unusual ability to infect two different types of cells critical to the immune defense arsenal in humans - T-cells and macrophages. T-cells can sense that foreign organisms have invaded the body, and quickly multiply and grow into small armies designed specifically to counterattack the invaders.

Macrophages perform a different, but equally important role. They roam the body independently, a bit like scavengers, seeking dead cells and bacteria to engulf and digest. They don't undergo cell division and rapidly multiply like T-cells. HIV's ability to infect both of these dividing and non-dividing cells is the reason scientists often refer to it as an "intelligent" virus. It's also the reason HIV is so deadly.

HIV attacks T-cells because every time these cells divide, they create another opportunity for the invading virus to replicate itself. T-cells try to defend the body by committing suicide, and they self-destruct so quickly that HIV would be eliminated if it didn't have the macrophages as a fallback.

"The purpose of every living organism is to survive, and HIV has brilliantly learned how to hide in macrophage cells over many years," says Baek Kim, UR professor of microbiology and immunology. Kim is the lead researcher on the miltefosine joint study between the UR Medical Center and the University of Utah School of Medicine. The peer-reviewed finding on the drug was published last month in the medical journal Retrovirology

"Think of the macrophages as little secret houses," says Kim. "They live a long time and they become little virus factories with reservoirs. In order for this to work, HIV found a way to extend the lives of the macrophages. They keep them alive. The question we've been asking is, how have they been able to keep them alive for so long?"

Kim, who has been working on HIV-related research for more than 15 years, says the answer has to do with what researchers call the "survivor pathway" in the macrophage cells. The pathway, which has also been studied by cancer researchers, normally regulates cell lifespan. But HIV has managed to manipulate the molecular reaction in the pathway, lengthening the macrophage's life. The drug miltefosine, Kim says, sabotages that process.

"We know that miltefosine can find the infected macrophage cell and, to use an expression, burn the house down," he says. "Without the macrophage cells to hide out in, HIV is exposed."

The beauty of the discovery, Kim says, is that the drug is not targeting HIV. It's targeting the abnormal cells that HIV lives inside.

"All the current drugs to combat HIV are good combative tools, but eventually HIV becomes resistant, which is a major problem," says Kim. "In this case, the virus is not able to become resistant to the drug."

Another feature of miltefosine, Kim says, is its ability to successfully enter the brain. The blood-brain barrier is the body's way of protecting its most important organ by screening some substances from entering brain tissue, while allowing others to flow freely. The problem for people with AIDS is getting drugs past the barrier, where HIV can hide out in infected macrophages without worry. Once inside the brain, the infected macrophages are capable of their worst mischief. They damage nearby brain cells or neurons, causing AIDS-related dementia. People don't usually die from the neurological disorder, but symptoms include forgetfulness, problems with motor coordination, and in its later stages, mania.

"Right now, you see, we can help people to live longer, but they don't live well," says Kim. "This drug can cross the blood-brain barrier and eliminate the damaged macrophages, and theoretically, we solve the problem of dementia."

At minimum, Kim says, the hope is miltefosine will give people a better quality of life - not just a longer life. But knowing how to eliminate HIV's secret hideouts could lead to something greater.

"We know how to increase the T-cells," says Kim. "Between this drug and what we've learned about the cell pathway, maybe someday we could increase the body's ability to fight back as if this were more like the flu virus - a virus with a shorter life. If we take away the long period of time the HIV infection is hidden, the body could defend itself. This discovery pushes the limit of what we know just a little bit farther."

Miltefosine is an existing drug, which helps to streamline the drug's approval process for use on HIV/AIDS patients.

"We still have to go to the NIH for funding," Kim says. "We still have to do the animal studies. But we expect they will support the findings, and we will go directly to human trials. We're probably looking at two to three years before the drug will be available for market."