Temple University and Children’s Hospital of Philadelphia (CHOP) have received a joint $4.3 million, four-year grant from the National Institute of Mental Health to investigate new methods to eradicate HIV that lurks in brain cells despite conventional antiviral treatments.
The neuroAIDS grant funds three research projects, each targeting different biological pathways crucial to the persistence of the human immunodeficiency virus that causes AIDS. Scientists from CHOP’s Section of Immunology and Temple’s Department of Neuroscience are collaborating on these studies to explore methods to enhance the immune system’s ability to attack HIV infection.
“This program represents a fresh look into a longstanding problem in HIV treatment—reservoirs of HIV within immune cells,” said Steven D. Douglas, professor of pediatrics and chief of the Section of Immunology at CHOP. “While current antiretroviral treatments can reduce the virus to undetectable levels, HIV persists latently inside cells. If drug treatment is interrupted, the virus comes surging back.”
Douglas and Jay Rappaport, professor of neuroscience and neurovirology at Temple University School of Medicine, are co–principal investigators of the new grant.
“All three projects seek to bypass vulnerabilities in the body’s immune system that are exploited by HIV,” said Rappaport. “By using biological tools to reinforce immune function, we aim to enable the immune system to eliminate HIV infection.”
During the first two years of the grant, the project teams will concentrate on basic biology to determine which preclinical approaches show the most promise for advancing the studies in the third and fourth years. The goal of this next phase will be to demonstrate proof of concept for strategies that could set the stage for human trials of innovative HIV treatments.
Project 1, led by Rappaport, focuses on the metabolism of ATP, the chemical that serves as energy currency in cells. Because HIV infection stimulates enzymes that degrade ATP and weaken immune responses, the research team will explore drug candidates that inhibit those enzymes.
Project 2, led by Tracy Fischer-Smith, assistant professor of neuroscience and neurovirology at Temple, concentrates on signaling proteins that drive immune polarization, in which cells called macrophages shift from protective roles to immune-suppressive activities. This team’s goal is to counteract those proteins’ signals and restore infection-fighting functions to immune cells.
Project 3, led by Douglas, investigates substance P, a neuropeptide with a key role in promoting inflammation during HIV infection. By manipulating a cell receptor that binds to substance P, the research team aims to disrupt HIV’s entry into cell reservoirs and to block the viral replication that accounts for HIV’s devastating effects.
“HIV infection disrupts immune cells by swinging a biological pendulum off balance into immune-suppressive activities that drive the disease,” said Fischer-Smith. “All three projects aim to modulate the immune system, inhibiting processes that are dangerously upregulated and restoring a healthy balance.”
This work is in collaboration with Temple’s Comprehensive NeuroAIDS Center and the Penn Mental Health AIDS Research Center at Penn Medicine and CHOP—two National Institutes of Health–supported centers concentrating on mental health and HIV.