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HTLV-1 Hbz protein, but not hbz mRNA secondary structure, is critical for viral persistence and disease development

Human T-cell leukemia virus type 1 (HTLV-1) is the etiologic cause of adult T-cell leukemia/lymphoma (ATL) and encodes a viral oncoprotein (Hbz) that is consistently expressed in asymptomatic carriers and ATL patients, suggesting its importance in the development and maintenance of HTLV-1 leukemic c...

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Autores principales: Maksimova, Victoria, Wilkie, Tasha, Smith, Susan, Phelps, Cameron, Melvin, Corrine, Yu, Lianbo, Niewiesk, Stefan, Green, Patrick L., Panfil, Amanda R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10309998/
https://www.ncbi.nlm.nih.gov/pubmed/37327244
http://dx.doi.org/10.1371/journal.ppat.1011459
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author Maksimova, Victoria
Wilkie, Tasha
Smith, Susan
Phelps, Cameron
Melvin, Corrine
Yu, Lianbo
Niewiesk, Stefan
Green, Patrick L.
Panfil, Amanda R.
author_facet Maksimova, Victoria
Wilkie, Tasha
Smith, Susan
Phelps, Cameron
Melvin, Corrine
Yu, Lianbo
Niewiesk, Stefan
Green, Patrick L.
Panfil, Amanda R.
author_sort Maksimova, Victoria
collection PubMed
description Human T-cell leukemia virus type 1 (HTLV-1) is the etiologic cause of adult T-cell leukemia/lymphoma (ATL) and encodes a viral oncoprotein (Hbz) that is consistently expressed in asymptomatic carriers and ATL patients, suggesting its importance in the development and maintenance of HTLV-1 leukemic cells. Our previous work found Hbz protein is dispensable for virus-mediated T-cell immortalization but enhances viral persistence. We and others have also shown that hbz mRNA promotes T-cell proliferation. In our current studies, we evaluated the role of hbz mRNA on HTLV-1-mediated immortalization in vitro as well as in vivo persistence and disease development. We generated mutant proviral clones to examine the individual contributions of hbz mRNA, hbz mRNA secondary structure (stem-loop), and Hbz protein. Wild-type (WT) and all mutant viruses produced virions and immortalized T-cells in vitro. Viral persistence and disease development were also evaluated in vivo by infection of a rabbit model and humanized immune system (HIS) mice, respectively. Proviral load and sense and antisense viral gene expression were significantly lower in rabbits infected with mutant viruses lacking Hbz protein compared to WT or virus with an altered hbz mRNA stem-loop (M3 mutant). HIS mice infected with Hbz protein-deficient viruses showed significantly increased survival times compared to animals infected with WT or M3 mutant virus. Altered hbz mRNA secondary structure, or loss of hbz mRNA or protein, has no significant effect on T-cell immortalization induced by HTLV-1 in vitro; however, the Hbz protein plays a critical role in establishing viral persistence and leukemogenesis in vivo.
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spelling pubmed-103099982023-06-30 HTLV-1 Hbz protein, but not hbz mRNA secondary structure, is critical for viral persistence and disease development Maksimova, Victoria Wilkie, Tasha Smith, Susan Phelps, Cameron Melvin, Corrine Yu, Lianbo Niewiesk, Stefan Green, Patrick L. Panfil, Amanda R. PLoS Pathog Research Article Human T-cell leukemia virus type 1 (HTLV-1) is the etiologic cause of adult T-cell leukemia/lymphoma (ATL) and encodes a viral oncoprotein (Hbz) that is consistently expressed in asymptomatic carriers and ATL patients, suggesting its importance in the development and maintenance of HTLV-1 leukemic cells. Our previous work found Hbz protein is dispensable for virus-mediated T-cell immortalization but enhances viral persistence. We and others have also shown that hbz mRNA promotes T-cell proliferation. In our current studies, we evaluated the role of hbz mRNA on HTLV-1-mediated immortalization in vitro as well as in vivo persistence and disease development. We generated mutant proviral clones to examine the individual contributions of hbz mRNA, hbz mRNA secondary structure (stem-loop), and Hbz protein. Wild-type (WT) and all mutant viruses produced virions and immortalized T-cells in vitro. Viral persistence and disease development were also evaluated in vivo by infection of a rabbit model and humanized immune system (HIS) mice, respectively. Proviral load and sense and antisense viral gene expression were significantly lower in rabbits infected with mutant viruses lacking Hbz protein compared to WT or virus with an altered hbz mRNA stem-loop (M3 mutant). HIS mice infected with Hbz protein-deficient viruses showed significantly increased survival times compared to animals infected with WT or M3 mutant virus. Altered hbz mRNA secondary structure, or loss of hbz mRNA or protein, has no significant effect on T-cell immortalization induced by HTLV-1 in vitro; however, the Hbz protein plays a critical role in establishing viral persistence and leukemogenesis in vivo. Public Library of Science 2023-06-16 /pmc/articles/PMC10309998/ /pubmed/37327244 http://dx.doi.org/10.1371/journal.ppat.1011459 Text en © 2023 Maksimova et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Maksimova, Victoria
Wilkie, Tasha
Smith, Susan
Phelps, Cameron
Melvin, Corrine
Yu, Lianbo
Niewiesk, Stefan
Green, Patrick L.
Panfil, Amanda R.
HTLV-1 Hbz protein, but not hbz mRNA secondary structure, is critical for viral persistence and disease development
title HTLV-1 Hbz protein, but not hbz mRNA secondary structure, is critical for viral persistence and disease development
title_full HTLV-1 Hbz protein, but not hbz mRNA secondary structure, is critical for viral persistence and disease development
title_fullStr HTLV-1 Hbz protein, but not hbz mRNA secondary structure, is critical for viral persistence and disease development
title_full_unstemmed HTLV-1 Hbz protein, but not hbz mRNA secondary structure, is critical for viral persistence and disease development
title_short HTLV-1 Hbz protein, but not hbz mRNA secondary structure, is critical for viral persistence and disease development
title_sort htlv-1 hbz protein, but not hbz mrna secondary structure, is critical for viral persistence and disease development
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10309998/
https://www.ncbi.nlm.nih.gov/pubmed/37327244
http://dx.doi.org/10.1371/journal.ppat.1011459
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