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

## TL;DR

This paper explores using IRF7 modulation to control HIV-1 latency, offering a new strategy to suppress the virus without immune activation.

## Contribution

The study introduces pacritinib as a novel latency-promoting agent that targets IRF7 to suppress HIV-1 transcription.

## Key findings

- Pacritinib suppresses HIV-1 latency reversal without immune activation.
- IRF7 downregulation by pacritinib correlates with reduced HIV-1 transcription.
- Pacritinib inhibits multiply spliced HIV-1 transcripts, blocking late transcriptional stages.

## Abstract

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).

The impact of JAK2i on HIV-1 reactivation, immune activation, and IRF7 expression were evaluated in lymphoid and myeloid HIV-1 latency models, as well as ex vivo CD4+ 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.

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.

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.