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

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.

3D Genome Plasticity in Normal and Diseased Neurodevelopment

“…Strikingly, microglia from brain tissue of individuals diagnosed with HIV encephalitis show a large scale reorganization of their chromosomal conformations, with altogether 192 megabases of microglial genome (exceeding the total length of human chromosome 5, to provide a dimensional perspective) affected. This is primarily driven by a shift of interferon-sensitive genes that are positioned within loci that convert into a more permissive open-chromatin-associated compartment status, as defined by significant changes in A/B compartment organization [ 73 ]. These microglia-specific 3D genome changes in the HIV infected human brain could be partially modeled by interferon stimulation of microglia in cell culture.…”

“…These microglia-specific 3D genome changes in the HIV infected human brain could be partially modeled by interferon stimulation of microglia in cell culture. Furthermore, many of the genomic loci that were newly mobilized into a more active compartment environment were at increased risk for being targeted for retroviral insertion, revealing a highly dynamic interrelationship of interferon-associated 3D genome and transcriptome remodeling with HIV integration in the brain [ 73 ].…”