HIV integration in the human brain is linked to microglial activation and 3D genome remodeling

• Published in: Molecular cell 2022-12, Vol.82 (24), p.4647-4663.e8
• Main Authors: Plaza-Jennings, Amara L., Valada, Aditi, O’Shea, Callan, Iskhakova, Marina, Hu, Benxia, Javidfar, Behnam, Ben Hutta, Gabriella, Lambert, Tova Y., Murray, Jacinta, Kassim, Bibi, Chandrasekaran, Sandhya, Chen, Benjamin K., Morgello, Susan, Won, Hyejung, Akbarian, Schahram
• Format: Article
• Language: English
• Subjects: Brain; chromosomal conformations; Hi-C; HIV encephalitis; HIV Infections - genetics; human immunodeficiency virus; Humans; interferon; Macrophage Activation; Macrophages; microglia; Microglia - metabolism; microglia-neuron interactions; retrovirus; single nuclei RNA-seq; viral integration
• ISSN: 1097-2765; 1097-4164; 1097-4164
• DOI: 10.1016/j.molcel.2022.11.016

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. [Display omitted] •Microglial 3D genome remodeling represses neural genes in HIV and HIV encephalitis•Further microglial 3D genome changes in HIV encephalitis are related to interferon stimulation•HIV targets genomic regions that switch to a more open state in HIV infection•HIV is actively transcribed in a subset of highly active microglia Plaza-Jennings et al. study HIV genome integration patterns in infected brain and link the spatial organization of the chromosomal material in brain immune cells to gene expression changes at single-cell resolution, including disruption of neuronal support functions and dynamic interrelations between neuroinflammation and viral insertion into the host genome.