NeuroAIDS Is Target of Federal Grant to Children's Hospital

A $6 million, five-year federal grant to The Children’s Hospital of Philadelphia Research Institute will enable researchers to investigate a novel approach in treating HIV infection--a unique class of drugs focused on developing therapies for psychological and neurological effects in AIDS.

Unlike many current HIV treatments, which are combinations of antiretroviral drugs, the compounds being studied cross into the brain, where HIV, the virus that causes AIDS, persists as a reservoir of infection, and causes dementia and cognitive impairments. In addition to studying the drug’s direct antiviral activity, the researchers will investigate its potential benefits in relieving depression-like symptoms in HIV-infected patients. They will also study whether the drug improves innate immunity.

The National Institute of Mental Health (NIMH) has awarded a cooperative program grant, classified as a U01 grant, entitled, “Anti-HIV Neuroimmodulatory Therapy with Neurokinin-1 Antagonists,” to a team led by principal investigator Steven D. Douglas, M.D., chief of the Section of Immunology and director of Clinical Immunology Laboratories at The Children’s Hospital of Philadelphia.

As program director, Douglas oversees projects within the grant led by collaborators from Children’s Hospital, the University of Pennsylvania School of Medicine, and the contract research organization Westat. This grant began Aug. 1, 2009.

At the heart of the program are drugs that target the neurokinin-1 receptor (NK1R) in human immune cells. Douglas and colleagues discovered in 1997 that human immune cells bear those cell receptors, and also produce substance P, a well-known neurotransmitter that binds to NK1R. In 2001, he showed in cell studies that an NK1R antagonist—a compound that binds to the NK1R receptor in immune cells—inhibits HIV from entering those cells by down-regulating, or dialing down the activity, of CCR5, a major HIV co-receptor on cell surfaces.

The current grant program will investigate the most effective ways to use NK1R antagonists to block HIV from replicating, with the aim of bringing those agents closer to use as clinical treatments. One project will use a specific NK-1R antagonist, the FDA-approved anti-nausea drug aprepitant, in a clinical trial in adult patients with HIV infection. It will be a Phase 1B trial, an early-stage test designed primarily to determine drug safety. It is also intended to test the concept that the drug may reduce virus levels in patients in whom highly active antiretroviral therapy (HAART) has failed.

“Our major goal is to establish proof-of-principle that this class of drug can reduce virus levels and otherwise benefit patients,” said Douglas. “We envision NK-1R antagonists as a potential key element of a combination therapy for patients with HIV infection.”

An estimated 50 percent of AIDS patients suffer some form of neuropsychiatric impairment, such as HIV-associated dementia, which is not well controlled by current antiretroviral drugs that have limited ability to cross the blood-brain barrier. Furthermore, while current drugs have improved patient survival, HIV continues to develop drug resistance, while neurocognitive deficits persist, compelling researchers to devise new antiviral therapies.