Modulation of IRF7-driven transcription as a strategy to control HIV-1 latency

Background: The persistence of latent HIV-1 reservoirs remains a major barrier to achieving a cure for HIV. While latency-reversing agents (LRAs) have been extensively studied, latency-promoting agents (LPAs) offer a complementary strategy to silence viral transcription and prevent immune activation. Here, we propose that modulation of IRF7-driven transcription may represent a novel approach to control HIV-1 latency, by characterizing the role of the Janus kinase 2 inhibitor (JAK2i) pacritinib as a novel latency-promoting agent (LPA). Methods: T cells from ART-suppressed individuals. IRF7 modulation was assessed by qRT-PCR and immunoblotting, and its functional role confirmed through LTR transactivation assays and IRF7 overexpression. Co-immunoprecipitation was used to detect IRF7-Tat interaction. Whole transcriptomic profiling with pathway analysis were performed to identify the molecular signatures associated with JAK2i treatment. Results: Pacritinib effectively suppressed HIV-1 latency reversal induced by LRAs without triggering immune activation. Mechanistically, pacritinib downregulated IRF7 expression at both transcript and protein levels, correlating with reduced HIV-1 transcription. Overexpression of IRF7 restored LTR transactivation, confirming its central role in HIV-1 transcription and latency. Co-immunoprecipitation assays revealed a direct interaction between IRF7 and the viral transactivator Tat. Furthermore, pacritinib selectively inhibited multiply spliced HIV-1 transcripts, suggesting a blockade at late transcriptional stages. Conclusion: Pacritinib acts as a potent LPA by silencing HIV-1 transcription through IRF7 downregulation, supporting a promising "block and lock" strategy for functional cure approaches. Targeting IRF7 may enable durable suppression of the viral reservoir without immune activation, supporting the development of "block and lock" therapies.