LA JOLLA, Calif., Feb. 25, 2021 /PRNewswire/ -- J. Craig Venter Institute (JCVI) scientists, led by Christine Cheng, Ph.D., have been awarded a $4.7 million, 5-year grant from the National Institute on Drug Abuse (NIDA), part of the National Institutes of Health (NIH), to study the effects of opioid abuse on the progression of HIV and its relationship to HIV-associated neurocognitive disorder (HAND). Dr. Cheng recently joined JCVI's faculty as an associate professor. The grant was originally awarded to her at Boston University and has been transferred to JCVI.
It is estimated that 12 million people globally inject drugs, of which 13% are HIV-positive. Opioid misuse is a route of contracting HIV and a barrier to effective antiretroviral therapy (ART). However, it is unclear whether opioid misuse changes the course of HIV pathogenesis, especially on HAND.
Persistent immune activation is the defining feature of HIV-1, the most common form of HIV, and a driver in the progression to AIDS. Persistent, systemic immune activation in people living with HIV has been hypothesized to account for higher incidence of chronic inflammatory diseases, including HAND.
While the virus reservoir in the central nervous system (CNS) is established with the primary infection, it takes years before the onset of significant neurological complications. Acute infection in the CNS is thought to initiate a cascade of pro-inflammatory events that result in inflammation-induced neuronal injuries and associated neurocognitive disorders.
Dr. Cheng said, "our central hypothesis is that opioid misuse exacerbates HIV pathogenesis in the CNS by dysregulating the glial cell population in the brain." Glial cells are found in the central nervous system, including the brain and spinal cord, and perform several important functions, including maintaining system balance, and providing support and protection for neurons.
To test this hypothesis, the team will catalog the effects of opioid use disorder on CNS neuronal and glial cells in individuals with HIV infections, including those with and without HAND. This will be accomplished by capturing gene expression data at the single nuclei level to identify dysregulated gene regulatory networks. Computational analysis will also be performed as part of this process.
Following data collection and analysis, the team will validate the most promising results using immunohistochemistry techniques on brain tissue samples (a process of selectively identifying antigens through staining). Based on these results, a subset will then be identified to characterize gene functionality using CRISPR knockout in 3D organoid-like models composed of neurons and glia cells.
Successful completion of these aims will have significant research and clinical impact by 1) determining how opioid misuse alters HIV/HAND pathogenesis in the CNS, and 2) discovering candidate molecules to regulate HIV infection or persistence in the CNS in the context of opioid misuse.
Suryaram Gummuluru, Ph.D., professor of microbiology, Boston University is also a principal investigator on this grant. His laboratory is studying interactions of HIV-1 with myeloid cells such as microglia and on the mechanisms of HIV-induced immune activation.
Funding for this work is provided by the National Institute on Drug Abuse (NIDA), National Institutes of Health (NIH), grant 7UM1DA051411-02.
About Dr. Christine Cheng
Christine S. Cheng is an associate professor in the informatics group at JCVI's La Jolla Campus. After completing her doctoral research, Dr. Cheng did her postdoctoral training with Dr. Aviv Regev at the Broad Institute of MIT and Harvard. Dr. Cheng's laboratory at JCVI includes both wet-lab (experimental) and dry-lab (computational) research. Dr. Cheng's research program studies transcriptional regulatory networks and aims to develop a comprehensive understanding of how aberrant regulatory circuits contribute to human disease.
Dr. Cheng's lab utilizes single-cell, droplet-based technology enabled by a microfluidic device to simultaneously profile the transcriptome and epigenome of thousands of single cells at the same time. The focus of her lab is to utilize single cell resolution functional genomic assays and computational methods to study heterogeneous clinical tissue samples and blood immune cell populations in patient samples.
Current projects focus on applying single-cell transcriptomics and epigenetics in Alzheimer's disease and opioid use disorder patient samples, with the goal of finding diagnostic markers and therapeutic targets.
About J. Craig Venter Institute
The J. Craig Venter Institute (JCVI) is a not-for-profit research institute in Rockville, Maryland and La Jolla, California. dedicated to the advancement of the science of genomics; the understanding of its implications for society; and communication of those results to the scientific community, the public, and policymakers. Founded by J. Craig Venter, PhD, the JCVI is home to approximately 150 scientists and staff with expertise in human and evolutionary biology, genetics, bioinformatics/informatics, information technology, high-throughput DNA sequencing, genomic and environmental policy research, and public education in science and science policy. The JCVI is a 501(c)(3) organization. For additional information, please visit www.JCVI.org.
SOURCE J. Craig Venter Institute