Temple Researchers Receive $7.4 Million Grant to Explore Brain Impairment in HIV-1 Patients
Researchers at Temple University School of Medicine (TUSM) have been awarded a $7.4 million, five-year grant from the National Institute on Drug Abuse to determine how cocaine and HIV-1 interact to cause brain impairment in patients infected with the human immunodeficiency virus.
Kamel Khalili, PhD, Chair of the Department of Neuroscience and Director of Temple's Comprehensive NeuroAIDS Center, will lead a multidisciplinary team examining how cocaine worsens the neurological deficits that can plague HIV patients as they age. Although this grant is directed toward untangling the complicated processes behind deterioration of central nervous system function in HIV-1, ultimately it may inform the discovery of future treatment for patients with neurocognitive disorders.
"This area of AIDS research is very novel and we are just scratching the surface in terms of scientific information and knowledge," Dr. Khalili said. "Through this grant, we hope to answer several important questions that could help in the next phase for the development of therapeutic molecules."
Dr. Khalili, a leader in the field of neuroAIDS, and recipient of many National Institutes of Health grants over the years, last summer showed how stowaway HIV genes might be snipped from inside infected cells for good, an important step toward a cure for the virus.
The newest grant reflects the investigator's steady focus on the effect of HIV-1 on the brain. "I have been interested in the central nervous system impact of HIV-1 since the very first days of the disease," Dr. Khalili said. "We soon realized that the impact is not as simple as the virus directly infecting neuronal cells, but rather a series of highly complicated events that lead to neuronal injury and death, and ultimately dysregulated brain function."
One complication is that HIV-1 cannot infect neurons. But the virus in the presence of cocaine manages to end-run this barrier by interfering with cell-to-cell communication and by damaging the tiny power plants within cells known as mitochondria, research in Dr. Khalili's lab has suggested. These power plants provide the essential energy for the work of the cell. Every cell in the body, except red blood cells, contains mitochondria, and every mitochondrion comes with its own DNA, something other organelles lack.
To attack neurons, HIV-1 first infects immune cells in the brain called macrophages and microglia. Once inside these immune cells, the virus hijacks their machinery, replicates itself, and produces a protein known as HIV-1 Tat. This protein in combination with cocaine, further impacts glial cells, whose function is important to the function and survival of neurons.
In the presence of cocaine, HIV-1 Tat stresses both glial cells and neurons, inducing them to make chemically reactive molecules containing oxygen, which harm the mitochondria’s DNA. Ultimately, the mitochondria die. Normally, cells clean up such damage efficiently, disposing of the damaged organelles and making new mitochondria to replace them. But HIV-1 Tat plus cocaine prevents the neuron from disposing of damaged mitochondria. Instead, the dead mitochondria accumulate, crippling the cell's ability to make replacement mitochondria. Eventually, lacking its mitochondrial energy source, the neuron dies. When many neurons die, loss of brain function is inevitable.
When the project is complete, Dr. Khalili hopes to have enough information to determine just where to focus potential treatments to disrupt this damaging pathway.
The research team includes experts in HIV-1 and neuroscience from the Comprehensive NeuroAIDS Center and Department of Neuroscience at TUSM and the Department of Biology in the College of Science and Technology at Temple University. It also includes investigators from the Center for Substance Abuse Research, experts in bioinformatics and biostatistics, and members of the Mitochondria Physiology and Imaging Core at the Center for Translational Medicine at TUSM. The team also includes investigators from the Icahn School of Medicine at Mount Sinai Hospital, New York, and Johns Hopkins School of Medicine, Baltimore.
In addition to Dr. Khalili, the Temple team is comprised of Shohreh Amini, Prasun Datta, John Elrod, Dianne Langford, Madesh Muniswamy, Jay Rappaport, Ellen Unterwald, Sara Ward and Huaqing Zhao.
The work was supported by National Institute on Drug Abuse grant 1P01DA037830-01A1.