U01DA053629

Single Cell Brain Transcriptome Changes During Chronic HIV Infection and Opiate Use in Conventional Mice - Project Summary

This application is submitted in response to RFA-D-21-019: Single Cell Opioid Responses in the Context of HIV (SCORCH) Program Expansion: CNS Data Generation for Chronic Opioid, Methamphetamine, and/or Cocaine Exposures.

Human Immunodeficiency Virus (HIV) can infect nonneuronal cells in the brain, particularly microglia, with these cells acting as a reservoir of latent infection. HIV infection has deleterious effects on the function of nonneuronal and neuronal cells, including those cells located in brain sites relevant to cognition, emotion, and motivation. The same brain sites impacted by HIV are known to regulate the actions of opioids and other classes of addictive drugs, and Opioid Use Disorder (OUD) is more prevalent in HIV-infected individuals than the general population. Moreover, HIV infection and OUD reciprocally interact, with each condition potentially exacerbating the severity of the other.

Mice infected with EcoHIV, a modified HIV strain that targets CD4+ T cells, macrophages, and microglia, recapitulate the major pathobiological features of chronic HIV infection in individuals on antiretroviral therapy (ART). Here, we will leverage state-of-the-art single cell sequencing (SCSeq), molecular, cellular, and behavioral approaches to define cell type-specific interactions between HIV and opioids in the brains of EcoHIV-infected mice.

In Specific Aim I, we optimize the intravenous (IV) heroin self-administration procedure, already well-established in our laboratories, for use in EcoHIV-infected mice. We will then examine the effects of EcoHIV infection on the expression of opioid addiction-relevant behaviors. Conversely, we will examine the effects of heroin consumption on the expression of cognitive abnormalities in EcoHIV-infected mice relevant to HIV-associated neurocognitive impairment (HIV-NCI) in humans. Finally, we will examine the effects of ART on the expression of addiction- and HIV-NCI-relevant behavioral abnormalities in EcoHIV-infected mice.

In Specific Aim II, we will perform SCSeq on brain regions relevant to opioid addiction and HIV-NCI, collected from EcoHIV mice with or without a history of intravenous opioid self-administration behavior. We will investigate the effects of ART on SCSeq patterns in these mice. The SCSeq data will be mined to identify cells in the brain infected by EcoHIV and determine which cells show the most robust transcriptional responses to EcoHIV in opioid-naïve and opioid-experienced mice. In situ hybridization and immunohistochemistry will be used to validate key findings and prioritize candidate genes for further investigation.

In Specific Aim III, we will use in vivo CRISPR-Cas9 to target prioritized genes identified in Aim II in a cell type- and brain region-specific manner. The impact of CRISPR cleavage of prioritized genes on the expression of addiction- and HIV-NCI-relevant behavioral abnormalities in EcoHIV-infected mice will be examined.

This innovative program of research may yield fundamental new insights into disease-relevant interactions between HIV infection and opioid drugs.

Icahn School Of Medicine At Mount Sinai

TO SUPPORT BASIC AND CLINICAL NEUROSCIENCE, BIOMEDICAL, BEHAVIORAL AND SOCIAL SCIENCE, EPIDEMIOLOGIC, HEALTH SERVICES AND HEALTH DISPARITY RESEARCH. TO DEVELOP NEW KNOWLEDGE AND APPROACHES RELATED TO THE PREVENTION, DIAGNOSIS, TREATMENT, ETIOLOGY, AND CONSEQUENCES OF DRUG ABUSE AND ADDICTION, INCLUDING HIV/AIDS. TO SUPPORT RESEARCH TRAINING AND RESEARCH SCIENTIST DEVELOPMENT. TO SUPPORT DISSEMINATION OF RESEARCH FINDINGS. SMALL BUSINESS INNOVATION RESEARCH (SBIR) LEGISLATION IS INTENDED TO EXPAND AND IMPROVE THE SBIR PROGRAMS TO EMPHASIZE AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF TECHNOLOGY DEVELOPED THROUGH FEDERAL SBIR RESEARCH AND DEVELOPMENT, INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN THE SBIR PROGRAM. THE LEGISLATION INTENDS THAT THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.279 - Drug Abuse and Addiction Research Programs

National Institute on Drug Abuse (NIDA) [HHS - NIH]

New York, New York 100296504 United States

Single Zip Code

Single Cell Opioid Responses in the Context of HIV (SCORCH) Program Expansion: CNS Data Generation for Chronic Opioid, Methamphetamine, and/or Cocaine Exposures (U01 Clinical Trial Not Allowed) (RFA-DA-21-019)

Amendment Since initial award the total obligations have increased 318% from $2,654,681 to $11,085,606.