In an effort to prevent HIV from developing into AIDS, infected patients must adhere to a drug regimen that over the years has proven difficult to follow. The therapy, called highly active anti-retroviral therapy, or HAART, is not effective for all patients and sometimes fails to control some of the neuropsychiatric problems experienced by nearly half of all patients with AIDS.
Although the existing regimen has improved the quality of life and longevity of those with HIV and AIDS, the therapy includes medicines that do not sufficiently cross from the blood and into the brain, where reservoirs of HIV exist. These virus pools often cause problems like dementia and a variety of cognitive problems.
Steven D. Douglas, MD, chief of the Section of Immunology and director of the Hospital’s Clinical Immunology Laboratories, continues to build upon his groundbreaking research to develop a novel HIV drug that targets the neurokinin-1 receptor (NK1R) in human immune cells to treat these HIV-related cognitive impairments, called NeuroAIDS.
More than a decade ago, Dr. Douglas and his colleagues found that immune cells in the human body have NK1R cell receptors and also produce a neurotransmitter called substance P that binds to the receptors. Later, Dr. Douglas found that an NK1R antagonist prevented HIV from entering those immune cells with the NK1R receptor. The antagonist inhibited HIV by impeding the activity of a major HIV co-receptor on cell surfaces called CCR5.
These seminal findings have paved the way for a potential new class of drugs used to treat the often severe psychological and neurological effects in NeuroAIDS. Dr. Douglas now leads a new $6 million cooperative program grant from the National Institute of Mental Health to find the most effective ways to use NK1R antagonists to block HIV replication.
“Our latest endeavor will look at the most effective ways to use NK1R antagonists to keep HIV from replicating,” says Dr. Douglas. “We will investigate not only the drug’s antiviral activity and its ability to relieve the symptoms associated with NeuroAIDS, but also whether it improves the body’s built-in, innate immunity.”
Aprepitant, a drug frequently used to prevent nausea, is one NK1R antagonist that Dr. Douglas and his colleagues are evaluating. The aprepitant study builds upon their recently completed laboratory and clinical investigations.
The new investigation involves cell studies, translational work to apply basic knowledge to treatments, and a clinical trial. Dr. Douglas and his team will look at how NK1R drugs function in both immune and brain cells, and they will investigate whether depression makes immune cells more vulnerable to HIV infection. The team will also evaluate whether aprepitant may prevent HIV from entering the cells while restoring the immune function of natural killer cells, a type of white blood cell that plays a critical role in immunity.
Dr. Douglas hopes the results of the new study will lead to a novel treatment for HIV and NeuroAIDS that he can bring to the clinical side of HIV care, in which he leads two worldwide therapeutic trials for pediatric and adult HIV and AIDS — the Philadelphia International Maternal Pediatric Adolescent AIDS Clinical Trials Unit and the Adolescent Trial Network.
The new project involves two clinical trials with aprepitant, one in HIV-infected adult patients receiving antiretroviral therapy, and the other combining the agent with the anti-HIV drug ritonavir in patients failing standard HIV therapy.
“NK1R antagonists in general have a lot of potential for new HIV treatments, but we still have a lot to learn about what they do and how they work,” says Dr. Douglas. “Our hope is that we can learn more about these promising agents, and rapidly translate our findings to a new therapeutic agent for HIV infection.”Back to top