Multiomics Profiling Reveals a Unique Chromatin Signature Associated with Active HIV-1 Proviruses

The three-dimensional structure of the genome is a key regulator of transcription; it is known that HIV-1 infection can influence host cell function, but the degree to which this is mediated at the level of changes to host chromatin architecture is not well understood. We interrogated genome-wide chromatin organization and the structure of chromatin around HIV-1 integration sites using Hi-C and ATAC-seq and combined these data with RNA transcriptional analysis of the provirus and neighboring genes in HIV-inducible cellular models. We found chromatin interaction networks around integrated HIV-1 are predominantly preserved with respect to uninfected cells, consistent with a lack of association between HIV-1 integration and major chromatin remodeling. Instead, we find that induction of proviral transcription leads to stark local changes in chromatin accessibility downstream from the HIV-1 3' LTR, demonstrating that HIV-1 can alter local cellular chromatin structure post-integration. Using long-read Nanopore RNA-seq, we interrogated the local host and HIV-1 transcriptomes and observe that 1-5% of HIV-1 transcripts initiated at the 5' LTR promoter, extend into the flanking cellular genome, generating chimeric virus-host RNAs. HIV-driven read-through resembles cellular stress-induced transcriptional reprogramming. Overall, integrated HIV-1 has only a modest effect on local cellular transcription and chromatin organization.