Immune Network Dysregulation of the Central Nervous System with HIV Persistence and Opioid Abuse

项目总结/文摘

PROJECT SUMMARY/ABSTRACT HIV persists within the body despite successful suppression of viral replication with antiretroviral therapy (ART), preventing eradication of the virus. Even a low level of persistent HIV in the brain may cause neurological damage, as 30-50% of well-suppressed HIV individuals under ART develop HIV-associated neurocognitive disorders (HAND). These abnormalities in the CNS are further complicated by opioid abuse, as opioid exposure results in exaggerated neuroinflammation. CNS immune activation induced by HIV and OUD is incompletely understood at the cellular level. Understanding the cellular basis for persistent CNS immune activation is critical for reducing neurological morbidities in the growing population of adults with HIV and OUD. Recent advances in massively parallel single cell RNA sequencing have uncovered numerous neuronal and glial populations widely across the central nervous system in health and disease. Such methods provide a powerful and unbiased way for understanding the organization of the cellular and immune network of the CNS based on transcriptional profiles at the single cell level. Here, we propose to employ state-of-the-art and novel methodologies in neuroscience, immunobiology, and computational biology to dissect the dysregulated immune network in the CNS of patients with HIV and OUD and the cell-type-specific response to opioid in the context of HIV. We will apply state-of-the-art single cell transcriptome analysis to uncover the molecular architecture and immune activation of the CSF in the patients with HIV and OUD. We will leverage our large dataset of human brain single nucleus RNA sequencing generated at the NIDA-supported CNS data generation center of Single Cell Opioid Responses in the Context of HIV at Yale (Y-SCORCH) to characterize the alterations of neuroimmune communications in OUD and HIV. We will develop and employ novel modern cell-type-specific approaches, such as ex vivo culture system, to determine the opioid responses of brain immune cell types, including microglia and brain-resident T cells, in the context of HIV. Determining the regulatory networks and molecular mechanisms of HIV persistence in response to opioid exposure will greatly advance our understanding of HIV latency and may provide novel insights and numerous pharmaceutical targets for treating HAND and eradicating HIV virus in HIV persistent individuals with opioid use disorder.