Mechanisms of HIV Latency in Hematopoietic Progenitors: GFI1 as a Key Regulator

ABSTRACT Durable control of HIV infection is challenged by persistent latent reservoirs, including hematopoietic stem and progenitor cells (HSPCs), which provide a unique niche for proviral silencing. Mechanisms of HIV latency in HSPCs remain poorly studied. Here, we utilized a dual-reporter HIV (89.6 VT1) and single-cell RNA sequencing to identify host factors governing latency in HSPCs. Transcriptomic profiling revealed elevated expression of several genes in latently infected cells, among them the transcriptional repressor GFI1. Functional studies showed that GFI1 suppresses HIV gene expression by binding a conserved sequence near the primer binding site within the long terminal repeat (LTR). Disruption of GFI1 DNA-binding or corepressor recruitment domains diminished its silencing effect. GFI1 also antagonized Tat and NF-κB-mediated activation, and reversal of GFI1-mediated suppression was most robust with combined HDAC inhibition and NF-κB activation. These findings position GFI1 as an important regulator of HIV latency in HSPCs.