Intragenic silencer regulates human retrovirus latency by recruiting RUNX1

Abstract Retroviruses integrate viral genome DNA into the host cellular genome. The integrated proviral DNA serves as a template for the production of progeny viruses. There are many points of similarity between two human retroviruses, human T-cell leukemia virus type 1 (HTLV-1) and human immunodeficiency virus type 1 (HIV-1), such as viral genome size, structure and targeting host cells; however, their natural course in infected individuals is remarkably different. HTLV-1 induces latent infection even in the absence of anti-retroviral drugs but enhances survival of the infected cells, resulting in cancer development. In contrast, HIV-1 infection causes vigorous viral production and keep high viremia in the blood, resulting in acquired immune deficiency syndrome. However, it still remains largely unknown why HTLV-1 prefers such latency phenotype in contrast with HIV-1. Here we identified a previously unidentified open chromatin region (OCR) in the middle of HTLV-1 provirus. We found the region functioned as a transcriptional silencer for the HTLV-1 5’-LTR promoter and thus named the OCR as retrovirus silencer region (RSR). RUNX1, a host transcription factor, and the co-factors localizes to the RSR and plays a pivotal role in the silencer function. The mutant virus containing mutations in the RSR that impaired RUNX1 binding showed higher proviral expression, virus production, persistence, and immunogenicity than wild type virus. Further, insertion of the RSR into recombinant HIV-1 remarkably decreased proviral expression, virus production and cytopathic effect. In conclusion, this study discovered retroviral silencer region that enables a human retrovirus HTLV-1 to co-exist with human for tens of thousands of years by hijacking RUNX1, a key regulator of cell lineage specification in the host cells and by establishing reversible latency in infected individuals. These findings not only open new avenues for treatment but also suggest an evolutionary perspective, indicating how HTLV-1 may have evolved a robust latency mechanism through the RSR, contributing to its unique pathogenesis.