HIV integration in the human brain is linked to microglial activation and 3D genome remodeling.
Publication/Presentation Date
12-15-2022
Abstract
To explore genome organization and function in the HIV-infected brain, we applied single-nuclei transcriptomics, cell-type-specific chromosomal conformation mapping, and viral integration site sequencing (IS-seq) to frontal cortex from individuals with encephalitis (HIVE) and without (HIV+). Derepressive changes in 3D genomic compartment structures in HIVE microglia were linked to the transcriptional activation of interferon (IFN) signaling and cell migratory pathways, while transcriptional downregulation and repressive compartmentalization of neuronal health and signaling genes occurred in both HIVE and HIV+ microglia. IS-seq recovered 1,221 brain integration sites showing distinct genomic patterns compared with peripheral lymphocytes, with enrichment for sequences newly mobilized into a permissive chromatin environment after infection. Viral transcription occurred in a subset of highly activated microglia comprising 0.33% of all nuclei in HIVE brain. Our findings point to disrupted microglia-neuronal interactions in HIV and link retroviral integration to remodeling of the microglial 3D genome during infection.
Volume
82
Issue
24
First Page
4647
Last Page
4663
ISSN
1097-4164
Published In/Presented At
Plaza-Jennings, A. L., Valada, A., O'Shea, C., Iskhakova, M., Hu, B., Javidfar, B., Ben Hutta, G., Lambert, T. Y., Murray, J., Kassim, B., Chandrasekaran, S., Chen, B. K., Morgello, S., Won, H., & Akbarian, S. (2022). HIV integration in the human brain is linked to microglial activation and 3D genome remodeling. Molecular cell, 82(24), 4647–4663.e8. https://doi.org/10.1016/j.molcel.2022.11.016
Disciplines
Medicine and Health Sciences
PubMedID
36525955
Department(s)
Medical Education
Document Type
Article