title: Functional Comparison of HBZ and the Related APH-2 Protein Provides Insight into Human T-Cell Leukemia Virus Type 1 Pathogenesis.
abstract: Human T-cell leukemia virus type 1 (HTLV-1) and type 2 (HTLV-2) are highly related retroviruses that transform T cells in vitro but have distinct pathological outcomes in vivo. 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 in vivo. In adult T-cell leukemia/lymphoma (ATL) cell lines and patient T cells, hbz 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 in vivo 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-κB (p65) transactivation, transforming growth factor β (TGF-β) 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-β 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.
  
  
  OBJECTIVE
  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 hbz and aph-2 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 in vivo 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-β signaling, NF-κB activation, and IRF-1 transactivation pathways.
authors.affiliation: Center for Retrovirus Research, The Ohio State University, Columbus, Ohio, USA Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Amanda R
authors.initials: AR
authors.lastname: Panfil
authors.affiliation: Center for Retrovirus Research, The Ohio State University, Columbus, Ohio, USA Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Nathan J
authors.initials: NJ
authors.lastname: Dissinger
authors.affiliation: Center for Retrovirus Research, The Ohio State University, Columbus, Ohio, USA Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Cory M
authors.initials: CM
authors.lastname: Howard
authors.affiliation: Center for Retrovirus Research, The Ohio State University, Columbus, Ohio, USA Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Brandon M
authors.initials: BM
authors.lastname: Murphy
authors.affiliation: Center for Retrovirus Research, The Ohio State University, Columbus, Ohio, USA Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Kristina
authors.initials: K
authors.lastname: Landes
authors.affiliation: Center for Biostatistics, The Ohio State University, Columbus, Ohio, USA Department of Biomedical Informatics, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Soledad A
authors.initials: SA
authors.lastname: Fernandez
authors.affiliation: Center for Retrovirus Research, The Ohio State University, Columbus, Ohio, USA Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio, USA Comprehensive Cancer Center and Solove Research Institute, The Ohio State University, Columbus, Ohio, USA Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, Ohio, USA green.466@osu.edu.
authors.forename: Patrick L
authors.initials: PL
authors.lastname: Green
mesh_terms: D002460:Cell Line; D015967:Gene Expression Regulation, Viral; D054884:Host-Pathogen Interactions; D015368:Human T-lymphotropic virus 1 / Q000472:pathogenicity / Q000502:physiology*; D006801:Humans; D060888:Real-Time Polymerase Chain Reaction; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors; D014764:Viral Proteins / Q000378:metabolism*
chemical_list: D051996:Transcription Factor RelA; D014764:Viral Proteins
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