{"doi":"10.1101/2022.05.03.490485","title":"HIV integration in the human brain is linked to microglial activation and 3D genome remodeling","abstract":"Abstract Exploration of genome organization and function in the HIV infected brain is critical to aid in the development of treatments for HIV-associated neurocognitive disorder (HAND) and HIV cure strategies. Here, we generated a resource comprised of single nuclei transcriptomics, complemented by cell-type-specific Hi-C chromosomal conformation (‘3D genome’) and viral integration site sequencing (IS-seq) in frontal brain tissues from individuals with HIV encephalitis (HIVE), HIV-infected people without encephalitis (HIV+), and HIV uninfected (HIV-) controls. We observed profound 3D genomic reorganization of open/repressive (A/B) compartment structures encompassing 6.4% of the HIVE microglial genome that was associated with transcriptomic reprogramming, including down-regulation of homeostasis and synapse-related functions and robust activation of interferon signaling and cell migratory pathways. HIV RNA was detected in 0.003% of all nuclei in HIVE brain, predominantly in the most activated microglia where it ranked as the second most highly expressed transcript. Microglia from HIV+ brains showed, to a lesser extent, similar transcriptional alterations. IS-seq recovered 1,221 insertion events in glial nuclei that were enriched for chromosomal domains newly mobilized into a permissive chromatin environment in HIVE microglia. Brain and peripheral myeloid cell integration revealed a preference overall for transcription-permissive chromatin, but robust differences in the frequency of recurrent insertions, intergenic integration, and enrichment for pre-integration complex-associated factors at integration sites. Our resource highlights critical differences in the genomic patterns of HIV infection in brain versus blood and points to a dynamic interrelationship between inflammation-associated 3D genome remodeling and successful integration in brain.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":299184,"datarank":0.3154918895607989,"base_score":1.6094379124341003,"endowment":1.6094379124341003,"self_citation_contribution":0.24141568686511508,"citation_network_contribution":0.0740762026956838,"self_endowment_contribution":0.24141568686511508,"citer_contribution":0.0740762026956838,"corpus_percentile":46.55372476212578,"corpus_rank":6910,"citation_count":4,"citer_count":3,"citers_with_citation_signal":3,"citers_with_endowment":3,"datacite_reuse_total":0,"is_dataset":true,"is_dataset_confidence":0.876,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":700492,"name":"Aditi Valada","orcid":"0000-0001-9001-215X","position":1,"is_corresponding":false},{"id":504264,"name":"Callan O’Shea","orcid":"0000-0003-1096-1983","position":2,"is_corresponding":false},{"id":460840,"name":"Marina Iskhakova","orcid":"0000-0002-4427-1334","position":3,"is_corresponding":false},{"id":873236,"name":"Benxia Hu","orcid":null,"position":4,"is_corresponding":false},{"id":460841,"name":"Behnam Javidfar","orcid":"0000-0003-2754-2742","position":5,"is_corresponding":false},{"id":462344,"name":"Gabriella Ben Hutta","orcid":null,"position":6,"is_corresponding":false},{"id":700491,"name":"Tova Y. Lambert","orcid":"0000-0002-5005-0087","position":7,"is_corresponding":false},{"id":873237,"name":"Jacinta Murray","orcid":null,"position":8,"is_corresponding":false},{"id":349771,"name":"Bibi Kassim","orcid":null,"position":9,"is_corresponding":false},{"id":460843,"name":"Sandhya Chandrasekaran","orcid":"0000-0003-1730-293X","position":10,"is_corresponding":false},{"id":397034,"name":"Benjamin K. Chen","orcid":"0000-0002-5404-1997","position":11,"is_corresponding":false},{"id":69471,"name":"Susan Morgello","orcid":"0000-0001-7729-245X","position":12,"is_corresponding":false},{"id":21503,"name":"Hyejung Won","orcid":"0000-0003-3651-0566","position":13,"is_corresponding":false},{"id":21362,"name":"Schahram Akbarian","orcid":"0000-0001-7700-0891","position":14,"is_corresponding":false},{"id":639035,"name":"Amara Plaza-Jennings","orcid":"0000-0002-7203-5507","position":0,"is_corresponding":true}],"reference_count":81,"raw_metadata":null,"created_at":"2026-07-19T00:31:40.528568Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}