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

Area of Science:

• Virology
• Immunology
• Molecular Biology

Background:

• Latent HIV-1 reservoirs are a significant obstacle to a functional cure.
• Latency-promoting agents (LPAs) offer a complementary strategy to latency-reversing agents (LRAs) by silencing viral transcription.
• Modulating Interferon Regulatory Factor 7 (IRF7) driven transcription is a potential novel approach to control HIV-1 latency.

Purpose of the Study:

• To characterize the Janus kinase 2 inhibitor (JAK2i) pacritinib as a novel LPA.
• To investigate the role of IRF7 in HIV-1 latency and transcription.
• To evaluate pacritinib's impact on HIV-1 reactivation, immune activation, and IRF7 expression.

Main Methods:

• Assessed pacritinib's impact on HIV-1 latency models and ex vivo CD4+ T cells.
• Quantified IRF7 expression using qRT-PCR and immunoblotting.
• Confirmed IRF7's functional role via LTR transactivation assays and overexpression studies; analyzed IRF7-Tat interaction using co-immunoprecipitation and whole transcriptomic profiling.

Main Results:

• Pacritinib suppressed LRA-induced HIV-1 latency reversal without immune activation.
• Pacritinib downregulated IRF7 at transcript and protein levels, reducing HIV-1 transcription.
• IRF7 overexpression restored LTR transactivation, and pacritinib inhibited multiply spliced HIV-1 transcripts, indicating late-stage transcriptional blockade.

Conclusions:

• Pacritinib functions as a potent LPA by silencing HIV-1 transcription via IRF7 downregulation.
• Targeting IRF7 offers a promising
• block and lock
• strategy for durable HIV reservoir suppression without immune activation.
• This supports the development of novel therapeutic approaches for a functional HIV cure.