HIV-1 active and latent infections induce disparate chromatin reorganization and transcriptional regulation of mRNAs and lncRNAs in SupT1 cells
Authors: Lê-Bury Gabrielle , Chen Yao , Rhen Jordan M. , Grenier Jennifer K. , Singhal Amit , Russell David G. , Boliar Saikat 
Published: December 2023

ABSTRACT

HIV-1 latency is a multi-dimensional, dynamic process, and many aspects of how the viral latency is established and maintained remain incompletely characterized. We have investigated how the host cellular epigenomic and transcriptomic microenvironments compare depending on the transcriptional state of the virus. Using a dual-reporter HIV
GKO
virus, we identified a significant divergence in chromatin reorganization and cellular gene expression patterns between active and latent HIV-1 infections of SupT1 cells. Latent HIV-1 infection induced significantly more cellular epigenomic restructuring than active infection. Furthermore, the nature of epigenomic changes also differed between the two states of HIV-1 infection. The majority of the changes in latent HIV-1 infection were repressive, whereas active viral infection led to an overall increase in chromatin accessibility. The repressed chromatin remodeling in latent infection was associated with the downregulation of genes involved in DNA replication, DNA repair, and cell cycle pathways, whereas the open chromatin structure in active infection led to increased expression of genes enriched for lipid metabolism, vesicle, and small molecule transport pathways. Similar to cellular mRNAs, our comprehensive transcriptomic analysis also identified a significant shift in long non-coding RNA (lncRNA) epigenomic and expression profiles between active and latent HIV-1 infections. Putative functional roles of novel lncRNAs associated with cellular pathways dysregulated in active and latent HIV-1 infections were identified, and the effects of viral reactivation on lncRNA expression in latently infected cells were evaluated. This study revealed that HIV-1 latent infection necessitates substantially greater alterations in the cellular epigenome and transcriptome than active HIV-1 infection.

IMPORTANCE

HIV-1 infection of T-lymphocytes depends on co-opting cellular transcriptional and translational machineries for viral replication. This requires significant changes in the cellular microenvironment. We have characterized and compared the changes in cellular chromatin structures as well as gene expression landscapes in T cells that are either actively or latently infected with HIV-1. Our results reveal that chromatin accessibility and expression of both protein-coding mRNAs and non-coding lncRNAs are uniquely regulated in HIV-1-infected T cells, depending on whether the virus is actively transcribing or remains in a transcriptionally silent, latent state. HIV-1 latent infection elicits more robust changes in the cellular chromatin organization than active viral infection. Our analysis also identifies the effects of such epigenomic changes on the cellular gene expression and subsequent biological pathways. This study comprehensively characterizes the cellular epigenomic and transcriptomic states that support active and latent HIV-1 infection in an
in vitro
model of SupT1 cells.