# Single molecule functional validation of neurogenomic alterations in opioid-exposed HIV brain

> **NIH DA R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2026 · $2,352,000

## Abstract

Neurogenomic studies by the SCORCH (Single Cell Opioid Response in the Context of HIV) consortium
strongly suggest that brains of individuals living with HIV in the context of opioid or (polys)substance use
disorder (OUD/SUD) comorbidity harbor a molecular environment permissive for HIV viral replication and risk
for cytotoxic damage. This conclusion also applied to donors who showed systemic, antiretroviral drug-
mediated suppression of the virus. There was a stepwise progression of transcriptomic dysregulation in
OUD+HIV+ brain, culminating in widespread neuronal pathology and pronounced inflammatory signatures in
microglia from individuals with poor viral suppression. The goals of the current project are two-fold. First, we
aim for single molecule validation of SCORCH single cell results, by analyzing~12-20kb single molecule fiber-
seq libraries from cingulate cortex of SCORCH brains carefully annotated for OUD/SUD and systemic (HIV)
suppression status. We will embark on single fiber-level multiomic profiling with differential analyses to
uncover effects of HIV infection on nucleosome phasing, positioning and offset at transcription start sites,
together with endogenous m5CpG methylation and transcription factor footprints. Integrating single cell
(RNA+ATAC-seq) data already generated from the same set of SCORCH brain cohort, with our new single
molecule multiomic fiber-seq mappings is expected to provide unprecedented neurogenomic insights into the
HIV and substance-exposed brain. Second, we aim for additional functional validation of SCORCH data, by
employing HIV-induced lineage tracing (HILT) in human induced pluripotent stem cell (hiPSC)-derived
Neuron-Astrocyte-Microglia (hiPSC N-A-Mg) tricultures, in conjunction with CRISPRi for multiplexed microglial
promoter repression focused on genes that are both (i) dysregulated in SCORCH SUD+ postmortem brain
and (ii) implicated in HIV expression or replication. We will assess viral integration frequency, numbers and

## Key facts

- **NIH application ID:** 11301614
- **Project number:** 1R01DA065015-01
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Schahram  Akbarian
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** DA
- **Fiscal year:** 2026
- **Award amount:** $2,352,000
- **Award type:** 1
- **Project period:** 2026-02-15T00:00:00 → 2030-01-31T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11301614

## Citation

> US National Institutes of Health, RePORTER application 11301614, Single molecule functional validation of neurogenomic alterations in opioid-exposed HIV brain (1R01DA065015-01). Retrieved via AI Analytics 2026-06-25 from https://api.ai-analytics.org/grant/nih/11301614. Licensed CC0.

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