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Integrated Human Neuroimmune Platforms to Define MECOM-Associated Microglial Mechanisms in HIV Persistence and Methamphetamine-Induced Neuroinflammation

Award Number: R61DA066158
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/15/2026
PERIOD OF PERFORMANCE END DATE: 03/31/2028

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Integrated Human Neuroimmune Platforms to Define MECOM-Associated Microglial Mechanisms in HIV Persistence and Methamphetamine-Induced Neuroinflammation - Abstract People with HIV (PWH) who use methamphetamine (METH) experience disproportionately high rates of neurocognitive impairment and chronic neuroinflammation, even with suppressive antiretroviral therapy. Microglia are central to these CNS complications, yet the molecular mechanisms by which METH exacerbates HIV-induced microglial dysfunction remain poorly understood. A major limitation in the field has been the lack of integrative, systems-level studies capable of identifying key molecular regulators of neuroinflammation and viral persistence in the context of HIV and substance use comorbidity. Our preliminary studies implicate MECOM (MDS1 and EVI1 complex locus protein), a stress-responsive transcriptional regulator, as a potential mediator of METH-induced microglial reprogramming under HIV infection. We observed that METH alters HIV replication and cytokine production in iPSC-derived microglia, with persistent effects following their integration into brain organoids. Bulk transcriptomic analyses revealed MECOM upregulation under HIV/METH co-exposure, suggesting a role in neuroimmune dysregulation. This proposal combines integrated transcriptomic and proteomic (multi-omics) analyses with advanced human-derived models, including iPSC-derived microglia, neuroimmune organoids, and HIV-infected humanized NOG-hIL34 mice, to map and validate MECOM- associated networks. We will first define MECOM-regulated signaling pathways and protein interaction networks in HIV-infected microglia exposed to METH using integrative transcriptomic and proteomic analyses. Building on these findings, we will then determine the functional consequences of MECOM deletion in human-derived in vitro models and in HIV-infected humanized mice. By uncovering how METH alters MECOM-dependent signaling in HIV-infected microglia, this study will provide new mechanistic insight into HIV-associated neuroinflammation and identify candidate molecular targets to mitigate CNS complications in PWH with comorbid substance use.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $668,423 )
2026	2026	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Drug Use and Addiction Research Programs	000	1	4/17/2026	NEW	$668,423
														Subtotal = $668,423

Grand Total All Awards = $668,423

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Integrated Human Neuroimmune Platforms to Define MECOM-Associated Microglial Mechanisms in HIV Persistence and Methamphetamine-Induced Neuroinflammation

Award Number: R61DA066158

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/15/2026

PERIOD OF PERFORMANCE END DATE: 03/31/2028

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