Grant to Explore Eradicating HIV from Hiding Places in the Brain

Exploring new methods to eradicate HIV that lingers in brain cells despite conventional antiviral treatment is the focus of a new study by investigators at Children’s Hospital and Temple University. They are the joint recipients of a $4.3 million, four-year NeuroAIDS grant from the National Institute of Mental Health.

The grant funds three research projects, each targeting different biological pathways crucial to the persistence of the human immunodeficiency virus that causes AIDS. Investigators from CHOP’s section of immunology and Temple’s department of neuroscience are collaborating on these cell and animal 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, MD, chief of the section of immunology at CHOP and a professor of pediatrics at the University of Pennsylvania. “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.”

Dr. Douglas and Jay Rappaport, PhD, 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 Dr. 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 pre-clinical approaches show the most promise for advancing into studies using animal models in the third and fourth years. The goal of the animal studies is to demonstrate proof-of-concept for strategies that could set the stage for subsequent human trials of innovative HIV treatments.

Project 1, led by Dr. 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, PhD, 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. The team’s goal is to counteract those proteins’ signals and restore infection-fighting functions to immune cells.

Project 3, led by Dr. Douglas, investigates substance P, a neuropeptide with a key role in promoting inflammation during HIV infection. By manipulating NK-1R, 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 Dr. Fischer-Smith. “All three projects aim to modulate the immune system, inhibiting processes that are dangerously up-regulated, and restoring a healthy balance.”

This work is in collaboration with the Penn Mental Health AIDS Research Center at Penn Medicine and CHOP, and Temple’s Comprehensive NeuroAIDS Center — two NIH-supported centers concentrating on mental health and HIV.

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