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.
Highlights
Human T-cell leukemia virus type 1 (HTLV-1) causes chronic infection leading to development of adult T-cell leukemia (ATL) and inflammatory diseases
Anti-chemokine receptor 4 (CCR4) antibody, which is currently used to treat ATL patients, was administered into simian T-cell leukemia virus type 1 (STLV-1)-infected Japanese macaques, and we found that this reduced the proviral load in vivo, indicating that anti-CCR4 antibody is effective for treatment of HTLV-1-associated inflammatory diseases
Functional similarity of STLV-1 Tax and STLV-1 bZIP factor to their counterparts in HTLV-1 Analysis of the STLV-1 pX region suggests the presence of tax coding gene and an antisense transcript in the minus strand of STLV-1 similar to HTLV-1 bZIP factor (HBZ)
Summary
Human 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. Human T-cell leukemia virus type 1 (HTLV-1) was the first human retrovirus found to cause a neoplastic disease, adult T-cell leukemia (ATL) [1,2]. HTLV-1 is endemic in specific areas including southwestern Japan, Central and South America, the Caribbean, The reason why most HTLV-1 carriers do not develop ATL is partly explained by the immune response of cytotoxic T cells (CTLs) against HTLV-1 proteins [8]. Two HTLV-1 proteins, Tax and HTLV-1 bZIP factor (HBZ), are thought to promote the proliferation of infected cells and ATL cells [4,11]. It has been reported that CTLs to HBZ play a critical role in determining proviral load in carriers [13]
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