Summary
The abuse of opioid drugs is associated with treatment non-compliance, greater risk of viral transmission,
and more rapid clinical progression of HIV disease. The overarching hypothesis behind the present project is
that the analysis of molecular profiles of neuronal and glia cells at the single cell level in drug abuse-relevant
brain regions by single nucleus RNA-Seq (snRNA-Seq) will reveal key genes that are dysregulated by the
interaction of HIV with opioid abuse, resulting in neurodegeneration and cognitive impairment. To test the
present hypothesis, we propose to use validated systems biology strategies for the reconstruction and
interrogation of a genome-scale integrated gene regulatory network in conjunction with snRNA-Seq from HIV
transgenic (Tg) rats, which harbor a non-replicating HIV-1 transgene expressing chronic low-levels of multiple
HIV-1 proteins in disease-relevant cell types, and wild-type rats.
The occasional but limited use of a drug is clinically distinct from dependent drug use, which is
characterized by the emergence of dependence and a negative emotional state when access to the drug is
prevented that drives negative reinforcement, a powerful source of motivation for drug seeking. Therefore, we
will use a state-of-the-art paradigm of voluntary intravenous opioid self-administration under short access
(ShA) conditions, which is characterized by a non-dependent, “recreational” pattern of drug use, and long
access (LgA) conditions, which leads to dependent drug intake. Escalated drug intake under LgA conditions is
highly relevant to human substance use disorder (SUD) as it has been suggested that it models all 7 of the
criteria for drug addiction in the Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV and 7 of the 11
criteria in the DSM-V. We showed that HIV Tg rats self-administering oxycodone in this LgA paradigm of
escalated self-administration display increased neural injury and cognitive impairment.
The project will address the following vexing question about opioid abuse in the setting of HIV infection:
what are the cell types and cell states that drive neuroinflammation, neurodegeneration, virus expression, and
escalated (dependent) opioid self-administration and cognitive impairment in the setting of HIV?
Overall, this collaborative interdisciplinary proposal integrating single cell level transcriptomics, state-of-the-
art behavior methods in HIV Tg and wild-type rats, and computational strategies for the deconvolution of the
gene regulatory network at the single cell level will elucidate key mechanisms that underlie the effects of HIV
and opioid abuse and their detrimental interactions on neuroHIV progression, virus expression and
persistence. The results will indicate transformative new mechanistic hypotheses that may lead to novel
therapeutic concepts for opioid use disorder (OUD) in the setting of HIV and will establish key resources for the
neuroHIV field to be made publicly available through the SCORCH data coordination center and other public
repositories.
