Nature Microbiology | Leukemia Virus (HTLV-1) Latency Regulation Mechanism and Potential Novel Therapeutic Targets

2025-08-20 75

Background

Human T-cell leukemia virus type 1 (HTLV-1), like human immunodeficiency virus type 1 (HIV-1), belongs to the Retroviridae family. It is the first identified human oncogenic retrovirus and shares similar genomic structure and target cells (CD4⁺ T cells) with HIV-1. However, it exhibits strikingly different infection kinetics. HTLV-1 does not rely on persistent viral replication to sustain infection; instead, it achieves long-term persistence by "hijacking host cell proliferation mechanisms" and may ultimately induce adult T-cell leukemia/lymphoma (ATL). HTLV-1 is endemic in Japan, the Caribbean, Central Africa, and South America. For decades, the molecular mechanism underlying HTLV-1's spontaneous establishment of reversible latency has remained elusive.

Fig.1 HIV-1 and HTLV-1 virion composition（Viruses. 2022 Jan 14;14(1):152.）

A team from Kumamoto University, Japan, published groundbreaking research in Nature Microbiology titled "Intragenic viral silencer element regulates HTLV-1 latency via RUNX complex recruitment", revealing the key molecular switch for HTLV-1's establishment of long-term latent infection! They identified an open chromatin region (OCR) within the HTLV-1 provirus. This OCR recruits the host transcription factor complex RUNX1-CBFβ and corepressors (HDAC3/Sin3A), forming a transcriptional silencing complex that actively suppresses the activity of the 5'-LTR promoter, thereby maintaining latency. This study aimed to elucidate the core regulatory mechanism of HTLV-1 latency and explore the evolutionary basis for the differences in infection strategies between HTLV-1 and HIV-1.

Research Content

1. Discovery of a Novel Silencer Element: The OCR

Using ATAC-seq analysis on peripheral blood mononuclear cells (PBMCs) from HTLV-1-infected individuals and ATL patient samples, the research team identified an open chromatin region within the HTLV-1 proviral pol gene for the first time. Luciferase reporter assays confirmed that the OCR specifically suppresses the promoter activity of the 5'-long terminal repeat (5'-LTR) while having no significant effect on 3'-LTR-driven antisense transcription. This indicates that the OCR likely plays a key transcriptional repressive role in HTLV-1's unique latency regulation and low replication efficiency! Notably, no structurally conserved intragenic silencer was found in HIV-1 or other deltaretroviruses (e.g., HTLV-2, BLV).

2. Host RUNX Complex Mediates Silencing Mechanism

Combining chromatin immunoprecipitation sequencing (ChIP-seq) with motif analysis revealed the central role of transcription factor families RUNX1, ETS1, and GATA3 binding to the OCR, suggesting this mechanism may be the core molecular switch for HTLV-1's lifelong latency:

·The RUNX1-CBFβ complex acts as the key effector, directly binding to 3 conserved sites within the OCR via its Runt domain.

·Corepressors HDAC3/Sin3A are recruited to the OCR, mediating histone deacetylation and chromatin compaction.

·ETS1 acts as a molecular "switch" by antagonizing RUNX1 function; its downregulation is associated with transcriptional bursts.

Fig.2 Molecular characterization of the silencer complex on the OCR

3. Validation of OCR's Role in Regulating Viral Latency

After constructing an HTLV-1 recombinant virus with mutated RUNX binding sites (s-mut), the following was observed:

·Tax mRNA expression increased by 52-fold, and viral particle production increased by 8-fold.

·Viral load continuously increased during long-term culture of the mutant virus, while the wild-type (WT) load decreased due to latency maintenance.

·Single-cell multiomics revealed that cells with an intact OCR formed a "latent cluster," while burst-state cells exhibited genome-wide chromatin openness.

Fig. 3 Virological and immunological significance of the OCR function in HTLV-1 infection

4. Immune Evasion and Therapeutic Intervention Potential

OCR silencing significantly reduces viral antigen exposure:

·Treatment with the RUNX1 inhibitor Ro5-3335 increased the Tax-positive rate in latent cells by 46-fold.

·Cells infected with the OCR mutant virus were cleared by cytotoxic T lymphocytes (CTLs) with 20-fold higher efficiency.

·Cross-virus experiments confirmed the OCR's universality: Insertion into the HIV-1 nef gene region reduced HIV-1 p24 expression by 80% and abolished cytopathic effects, demonstrating that this element can reconfigure retroviral replication dynamics.

Fig. 4 Introduction of HTLV-1 OCR into rHIV-1 decreases proviral expression, virus production and cytopathic effect

Conclusions and Significance

This study is the first to elucidate the core mechanism by which HTLV-1 actively hijacks the host RUNX1-CBFβ-HDAC3/Sin3A complex via an "intragenic silencer" (OCR) to establish reversible latency:

Theoretical Level: Explains HTLV-1's unique strategy of relying on infected cell clonal expansion (rather than viral replication) for persistent infection, providing a new paradigm for virus-host co-evolution research.

Therapeutic Level: Targeting the OCR-RUNX1 interaction can specifically activate the latent viral reservoir, offering a novel target for combined immune clearance therapies.

Technical Level: The successful transplantation of the HTLV-1 silencer element into HIV-1 lays the foundation for engineering artificial latency regulation tools.

This study fills a critical knowledge gap in the latency mechanisms of exogenous retroviruses and has landmark significance for ATL prevention strategies and the development of latency reversal therapies!

References

1. Kalinichenko S, Komkov D, Mazurov D. HIV-1 and HTLV-1 Transmission Modes: Mechanisms and Importance for Virus Spread. Viruses. 2022;14(1):152.
2. Kenji Sugata, Rahman A, Koki Niimura, et al. Intragenic viral silencer element regulates HTLV-1 latency via RUNX complex recruitment. Nature Microbiology. Published online May 13, 2025.

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