Characterization of simian T-cell leukemia virus type 1 in naturally infected Japanese macaques as a model of HTLV-1 infection

Abstract

BackgroundHuman T-cell leukemia virus type 1 (HTLV-1) causes chronic infection leading to development of adult T-cell leukemia (ATL) and inflammatory diseases. Non-human primates infected with simian T-cell leukemia virus type 1 (STLV-1) are considered to constitute a suitable animal model for HTLV-1 research. However, the function of the regulatory and accessory genes of STLV-1 has not been analyzed in detail. In this study, STLV-1 in naturally infected Japanese macaques was analyzed.ResultsWe identified spliced transcripts of STLV-1 corresponding to HTLV-1 tax and HTLV-1 bZIP factor (HBZ). STLV-1 Tax activated the NFAT, AP-1 and NF-κB signaling pathways, whereas STLV-1 bZIP factor (SBZ) suppressed them. Conversely, SBZ enhanced TGF-β signaling and induced Foxp3 expression. Furthermore, STLV-1 Tax activated the canonical Wnt pathway while SBZ suppressed it. STLV-1 Tax enhanced the viral promoter activity while SBZ suppressed its activation. Then we addressed the clonal proliferation of STLV-1+ cells by massively sequencing the provirus integration sites. Some clones proliferated distinctively in monkeys with higher STLV-1 proviral loads. Notably, one of the monkeys surveyed in this study developed T-cell lymphoma in the brain; STLV-1 provirus was integrated in the lymphoma cell genome. When anti-CCR4 antibody, mogamulizumab, was administered into STLV-1-infected monkeys, the proviral load decreased dramatically within 2 weeks. We observed that some abundant clones recovered after discontinuation of mogamulizumab administration.ConclusionsSTLV-1 Tax and SBZ have functions similar to those of their counterparts in HTLV-1. This study demonstrates that Japanese macaques naturally infected with STLV-1 resemble HTLV-1 carriers and are a suitable model for the investigation of persistent HTLV-1 infection and asymptomatic HTLV-1 carrier state. Using these animals, we verified that mogamulizumab, which is currently used as a drug for relapsed ATL, is also effective in reducing the proviral load in asymptomatic individuals.

TCF1 and LEF1 act as T-cell intrinsic HTLV-1 antagonists by targeting Tax

“…Higher STLV-1 encoded Tax and STLV-1 bZIP factor (SBZ) possess functions similar to those of HTLV-1 Tax and HBZ, and an STLV-1-infected Japanese macaque developed T-cell lymphoma (26), indicating that STLV-1-infected Japanese macaques can serve as a suitable model of HTLV-1 infection. STLV-1 Tax is highly homologous to HTLV-1 Tax (26).…”

“…STLV-1-infected Japanese macaque has been demonstrated to be a suitable model for HTLV-1 infection (26). It also served as an ideal model to analyze the impact of the antagonism of TCF1/LEF1 against Tax in vivo.…”

Enhancement of anti-STLV-1/HTLV-1 immune responses through multimodal effects of anti-CCR4 antibody

“…(Mf-6 and Mf-7 in our previous study were renamed JM10 and JM11, respectively17.) STLV-1-infected JMs were screened using the Serodia HTLV-1 kit (Fuji Rebio), and provirus load was measured by real-time PCR.…”

The sense behind retroviral anti-sense transcription

“…Antisense transcription is not exclusive to HIV and HTLV, and has also been reported in the deltaretroviruses bovine leukemia virus (BLV) [42] and simian T-cell leukemia virus (STLV) [43], the lentiviruses feline immunodeficiency virus (FIV) [44] and bovine immunodeficiency virus (BIV) [45], as well as the gammaretrovirus murine leukemia virus (MLV) [46]. However, the regulation of antisense transcription remains poorly studied in these retroviruses.…”