{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T17:02:58Z","timestamp":1791306178963,"version":"4.3.1"},"reference-count":66,"publisher":"American Society for Microbiology","issue":"7","license":[{"start":{"date-parts":[[2016,4,1]],"date-time":"2016-04-01T00:00:00Z","timestamp":1459468800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/100000002","name":"HHS | National Institutes of Health","doi-asserted-by":"publisher","award":["CA100730"],"award-info":[{"award-number":["CA100730"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"HHS | National Institutes of Health","doi-asserted-by":"publisher","award":["AI095913"],"award-info":[{"award-number":["AI095913"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["J Virol"],"published-print":{"date-parts":[[2016,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Human T-cell leukemia virus type 1 (HTLV-1) and type 2 (HTLV-2) are highly related retroviruses that transform T cells\n                    <jats:italic>in vitro<\/jats:italic>\n                    but have distinct pathological outcomes\n                    <jats:italic>in vivo<\/jats:italic>\n                    . HTLV-1 encodes a protein from the antisense strand of its proviral genome, the HTLV-1 basic leucine zipper factor (HBZ), which inhibits Tax-1-mediated viral transcription and promotes cell proliferation, a high proviral load, and persistence\n                    <jats:italic>in vivo<\/jats:italic>\n                    . In adult T-cell leukemia\/lymphoma (ATL) cell lines and patient T cells,\n                    <jats:italic>hbz<\/jats:italic>\n                    is often the only viral gene expressed. The antisense strand of the HTLV-2 proviral genome also encodes a protein termed APH-2. Like HBZ, APH-2 is able to inhibit Tax-2-mediated viral transcription and is detectable in most primary lymphocytes from HTLV-2-infected patients. However, unlike HBZ, the loss of APH-2\n                    <jats:italic>in vivo<\/jats:italic>\n                    results in increased viral replication and proviral loads, suggesting that HBZ and APH-2 modulate the virus and cellular pathways differently. Herein, we examined the effect of APH-2 on several known HBZ-modulated pathways: NF-\u03baB (p65) transactivation, transforming growth factor \u03b2 (TGF-\u03b2) signaling, and interferon regulatory factor 1 (IRF-1) transactivation. Like HBZ, APH-2 has the ability to inhibit p65 transactivation. Conversely, HBZ and APH-2 have divergent effects on TGF-\u03b2 signaling and IRF-1 transactivation. Quantitative PCR and protein half-life experiments revealed a substantial disparity between HBZ and APH-2 transcript levels and protein stability, respectively. Taken together, our data further elucidate the functional differences between HBZ and APH-2 and how these differences can have profound effects on the survival of infected cells and, ultimately, pathogenesis.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>IMPORTANCE<\/jats:bold>\n                    Human T-cell leukemia virus type 1 (HTLV-1) and type 2 (HTLV-2) are highly related retroviruses that have distinct pathological outcomes in infected hosts. Functional comparisons of HTLV-1 and HTLV-2 proteins provide a better understanding about how HTLV-1 infection is associated with disease and HTLV-2 infection is not. The HTLV genome antisense-strand genes\n                    <jats:italic>hbz<\/jats:italic>\n                    and\n                    <jats:italic>aph-2<\/jats:italic>\n                    are often the only viral genes expressed in HTLV-infected T cells. Previously, our group found that HTLV-1 HBZ and HTLV-2 APH-2 had distinct effects\n                    <jats:italic>in vivo<\/jats:italic>\n                    and hypothesized that the differences in the interactions of HBZ and APH-2 with important cell signaling pathways dictate whether cells undergo proliferation, apoptosis, or senescence. Ultimately, these functional differences may affect how HTLV-1 causes disease but HTLV-2 generally does not. In the current study, we compared the effects of HBZ and APH-2 on several HTLV-relevant cellular pathways, including the TGF-\u03b2 signaling, NF-\u03baB activation, and IRF-1 transactivation pathways.\n                  <\/jats:p>","DOI":"10.1128\/jvi.03113-15","type":"journal-article","created":{"date-parts":[[2016,1,27]],"date-time":"2016-01-27T22:14:03Z","timestamp":1453932843000},"page":"3760-3772","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":37,"title":["Functional Comparison of HBZ and the Related APH-2 Protein Provides Insight into Human T-Cell Leukemia Virus Type 1 Pathogenesis"],"prefix":"10.1128","volume":"90","author":[{"given":"Amanda R.","family":"Panfil","sequence":"first","affiliation":[{"name":"Center for Retrovirus Research, The Ohio State University, Columbus, Ohio, USA"},{"name":"Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathan J.","family":"Dissinger","sequence":"additional","affiliation":[{"name":"Center for Retrovirus Research, The Ohio State University, Columbus, Ohio, USA"},{"name":"Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cory M.","family":"Howard","sequence":"additional","affiliation":[{"name":"Center for Retrovirus Research, The Ohio State University, Columbus, Ohio, USA"},{"name":"Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brandon M.","family":"Murphy","sequence":"additional","affiliation":[{"name":"Center for Retrovirus Research, The Ohio State University, Columbus, Ohio, USA"},{"name":"Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristina","family":"Landes","sequence":"additional","affiliation":[{"name":"Center for Retrovirus Research, The Ohio State University, Columbus, Ohio, USA"},{"name":"Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soledad A.","family":"Fernandez","sequence":"additional","affiliation":[{"name":"Center for Biostatistics, The Ohio State University, Columbus, Ohio, USA"},{"name":"Department of Biomedical Informatics, The Ohio State University, Columbus, Ohio, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick L.","family":"Green","sequence":"additional","affiliation":[{"name":"Center for Retrovirus Research, The Ohio State University, Columbus, Ohio, USA"},{"name":"Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio, USA"},{"name":"Comprehensive Cancer Center and Solove Research Institute, The Ohio State University, Columbus, Ohio, USA"},{"name":"Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, Ohio, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1208968"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.78.10.6476"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.79.6.2031"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(85)92734-5"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(86)91298-5"},{"key":"e_1_3_2_7_2","first-page":"2071","volume-title":"Fields virology","author":"Lairmore M","year":"2007","unstructured":"Lairmore M, Franchini G. 2007. 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