Single nuclei transcriptome profiling in addiction circuitry of the HIV+ brain

HIV-associated neurocognitive disorders (HAND) persist in the era of combination antiretroviral
therapy (cART). HIV latency, and cell-specific expression of HIV transcript in human CNS remains
incompletely understood, despite continued high prevalence of HIV-associated neurologic disease and
increasing recognition of CNS viral escape in people stably suppressed with cART. One of the major
issues regarding CNS HIV in need for study is HIV integration. With other words, whether CNS HIV
integration has biologically significant impact, contributing to pathogenesis? Issues of CNS functional
deficit are further complicated by the co-registered epidemic of opiate and other substance use
disorders (SUD) in people living with HIV/AIDS (PLWHA), as SUD also have profound impact on CNS
function, and potentially on HIV latency. Nowhere in the CNS is this more evident than in the
neuroanatomic overlap of HIV and SUD in striatonigral dopaminergic circuitry and frontostriatal
projections, sites of predilection for functional and neurobiologic disease as well as for increased burden
of HIV infection. Accordingly, directly utilizing brain tissues in these regions, from neurologically well-
characterized HIV-infected individuals with and without SUD, the goal of this application will be: (i) to
replicate for brain some of the emerging genomic mechanisms recently discovered in peripheral cells,
linking HIV host genome integration and virus latency to nuclear topography and open chromatin; (ii) to
explore whether HIV signatures in transcriptomes and epigenomes in dopaminergic circuitry
including frontal and striatal targets is associated with prospectively monitored neurological
status in the years before death and exposure to drug of abuse; (iii) explore HIV expression in potential
reservoir cells of the brain, including microglia. The innovative experiments proposed here are expected
to offer novel insights into transcriptomic landscapes in specific brain cells and explore potential links
between neurogenomic status of the infected brain and neurological and cognitive symptoms and
substance abuse. While recognizing the high-risk aspects, these analyses will nevertheless have
predictable, high gain benefits in understanding the complex neurobiology underlying HIV-
associated CNS disease in PLWHA and SUD.

Grant Number: 5U01DA053600-05
NIH Institute/Center: NIH
Principal Investigator: Schahram Akbarian