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

Miura M, Yasunaga J, Tanabe J, Sugata K, Zhao T, Ma G, Miyazato P, Ohshima K, Kaneko A, Watanabe A, Saito A, Akari H, Matsuoka M - Retrovirology (2013)

Bottom Line: STLV-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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Laboratory of Virus Control, Institute for Virus Research, Kyoto University, Shogoin Kawahara-cho 53, Sakyo-ku, Kyoto 606-8507, Japan. mmatsuok@virus.kyoto-u.ac.jp.

ABSTRACT

Background: 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. 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.

Results: We 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.

Conclusions: STLV-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.

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Effect of anti-CCR4 antibody on STLV-1 dynamics in vivo. (A) CD3+CD4+ T cells were gated and the expression of CCR4 was analyzed by flow cytometry. (B) Changes in STLV-1 proviral load in two monkeys treated with anti-CCR4 antibody until week 3. (C) Absolute cell numbers of the five most abundant clones in 1,000,000 PBMCs at weeks 0, 5 and 18 are shown.
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Figure 7: Effect of anti-CCR4 antibody on STLV-1 dynamics in vivo. (A) CD3+CD4+ T cells were gated and the expression of CCR4 was analyzed by flow cytometry. (B) Changes in STLV-1 proviral load in two monkeys treated with anti-CCR4 antibody until week 3. (C) Absolute cell numbers of the five most abundant clones in 1,000,000 PBMCs at weeks 0, 5 and 18 are shown.

Mentions: ATL cells express high levels of CC chemokine receptor 4 (CCR4) [28]. Recently, mogamulizumab, a humanized IgG1 monoclonal antibody against CCR4 [29], was approved in Japan for the treatment of relapsed ATL patients. HTLV-1-infected cells of healthy carriers also express CCR4, which indicates that mogamulizumab likely reduces the proviral load in HTLV-1-infected asymptomatic individuals [30]. High proviral load has been reported to be associated with HAM/TSP, HTLV-1 uveitis, and risk of ATL, indicating that mogamulizumab may potentially be used for the treatment of HTLV-1-associated diseases and the prevention of ATL. However, it is not clear whether mogamulizumab can reduce the proviral load in HTLV-1-infected individuals. We confirmed that mogamulizumab also recognizes macaque CCR4 by staining Japanese macaque PBMCs in vitro with the fluorescently labeled antibody (see Additional file 3). Then, we tested the efficacy of mogamulizumab to reduce the proviral load in STLV-1-infected Japanese macaques. Mogamulizumab was administered to two monkeys with high proviral load (Mf-6 and Mf-7), once a week for 4 weeks. As shown in Figure 7A, nearly half of the CD4+ T cells expressed CCR4 before the treatment (week 0). After the treatment, the CCR4 positivity decreased to 1.62% and 12.4% respectively. We also measured proviral load over the course of the treatment and found that it decreased dramatically within 2 weeks (Figure 7B). Thus, this demonstrates that mogamulizumab can indeed reduce the number of STLV-1-infected cells in vivo.


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

Miura M, Yasunaga J, Tanabe J, Sugata K, Zhao T, Ma G, Miyazato P, Ohshima K, Kaneko A, Watanabe A, Saito A, Akari H, Matsuoka M - Retrovirology (2013)

Effect of anti-CCR4 antibody on STLV-1 dynamics in vivo. (A) CD3+CD4+ T cells were gated and the expression of CCR4 was analyzed by flow cytometry. (B) Changes in STLV-1 proviral load in two monkeys treated with anti-CCR4 antibody until week 3. (C) Absolute cell numbers of the five most abundant clones in 1,000,000 PBMCs at weeks 0, 5 and 18 are shown.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4016002&req=5

Figure 7: Effect of anti-CCR4 antibody on STLV-1 dynamics in vivo. (A) CD3+CD4+ T cells were gated and the expression of CCR4 was analyzed by flow cytometry. (B) Changes in STLV-1 proviral load in two monkeys treated with anti-CCR4 antibody until week 3. (C) Absolute cell numbers of the five most abundant clones in 1,000,000 PBMCs at weeks 0, 5 and 18 are shown.
Mentions: ATL cells express high levels of CC chemokine receptor 4 (CCR4) [28]. Recently, mogamulizumab, a humanized IgG1 monoclonal antibody against CCR4 [29], was approved in Japan for the treatment of relapsed ATL patients. HTLV-1-infected cells of healthy carriers also express CCR4, which indicates that mogamulizumab likely reduces the proviral load in HTLV-1-infected asymptomatic individuals [30]. High proviral load has been reported to be associated with HAM/TSP, HTLV-1 uveitis, and risk of ATL, indicating that mogamulizumab may potentially be used for the treatment of HTLV-1-associated diseases and the prevention of ATL. However, it is not clear whether mogamulizumab can reduce the proviral load in HTLV-1-infected individuals. We confirmed that mogamulizumab also recognizes macaque CCR4 by staining Japanese macaque PBMCs in vitro with the fluorescently labeled antibody (see Additional file 3). Then, we tested the efficacy of mogamulizumab to reduce the proviral load in STLV-1-infected Japanese macaques. Mogamulizumab was administered to two monkeys with high proviral load (Mf-6 and Mf-7), once a week for 4 weeks. As shown in Figure 7A, nearly half of the CD4+ T cells expressed CCR4 before the treatment (week 0). After the treatment, the CCR4 positivity decreased to 1.62% and 12.4% respectively. We also measured proviral load over the course of the treatment and found that it decreased dramatically within 2 weeks (Figure 7B). Thus, this demonstrates that mogamulizumab can indeed reduce the number of STLV-1-infected cells in vivo.

Bottom Line: STLV-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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Laboratory of Virus Control, Institute for Virus Research, Kyoto University, Shogoin Kawahara-cho 53, Sakyo-ku, Kyoto 606-8507, Japan. mmatsuok@virus.kyoto-u.ac.jp.

ABSTRACT

Background: 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. 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.

Results: We 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.

Conclusions: STLV-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.

Show MeSH
Related in: MedlinePlus