Novel HIV drug to be studied in cell cultures and patients

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.

NK1R antagonists show promise as potential new treatments, but much remains to be learned about their biology and activity. Douglas's new grant encompasses cell studies, translational work to apply basic knowledge to treatments, and a clinical trial. The new grant builds on a previous four-year NIMH grant just concluding. That grant included an animal study that showed aprepitant was tolerated in rhesus macaque monkeys. The grant also supported a double-blind clinical trial of aprepitant in human subjects, with results due to be reported late this year.

In the new grant, one project focuses on cellular mechanisms-how NK-1R drugs function in human immune cells and brain cells. The project leader is John Wolfe, V.M.D., Ph.D., a Children's Hospital of Philadelphia Research Institute scientist and a Penn professor of Pathology and Medical Genetics with special expertise in genetic and cellular mechanisms in the brain.

A second project addresses immune mechanisms, investigating whether clinical depression makes a person's immune cells more vulnerable to HIV infection. The researchers will also study how aprepitant may have a dual effect, both preventing HIV from entering cells and restoring the immune function of natural killer cells. People with depression show lower levels of natural killer cells, and NK1R drugs may act against depressive behavior. Douglas leads this project, working with co-investigators Jordan Orange, M.D., Ph.D., of Children's Hospital, an expert in natural killer cells, and Dwight Evans, M.D., chair of Psychiatry at the Penn School of Medicine. Evans is internationally prominent for studying the connections between depression and immune function.

The third project is a Phase 1B clinical trial, to be led by Pablo Tebas, M.D., clinical research site principal investigator of the AIDS Clinical Trials Unit at the Hospital of the University of Pennsylvania. That unit participates in IMPAACT--the International Maternal Pediatric Adolescent AIDS Clinical Trials Group, of which Douglas is the overall principal investigator for IMPAACT's Philadelphia Clinical Trials Unit.

The trial, to be conducted in HIV-infected adult patients already receiving antiretroviral medicines, will test the safety of aprepitant in those patients. A second clinical study will test aprepitant as an antiviral agent in combination with ritonavir, another anti-HIV drug, in patients failing HIV therapy. The interactions between both drugs may strengthen the effects of aprepitant without increasing its dosage. The trial will measure antiviral activity as well as changes in depressive behavior and anxiety among the subjects.

Although aprepitant has a central role in the study projects, it may not ultimately be the drug used in future HIV clinics. "Aprepitant is the only FDA-approved drug among NK1R antagonists, but we expect that ultimately another compound in the same class will become a new anti-AIDS drug," says Florin Tuluc, M.D., Ph.D., of Children's Hospital, an expert on cell signaling who is a collaborator in the program. "We believe a NK1R antagonist will have an important role as a novel medicine in treating neuroAIDS."