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    Complex Interplay of the UL136 Isoforms Balances Cytomegalovirus Replication and Latency

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    mBio-2016-Caviness-.pdf
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    2.185Mb
    Format:
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    Description:
    Final Published Version
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    Author
    Caviness, Katie
    Bughio, Farah
    Crawford, Lindsey B.
    Streblow, Daniel N.
    Nelson, Jay A.
    Caposio, Patrizia
    Goodrum, Felicia
    Affiliation
    Univ Arizona, Grad Interdisciplinary Program Genet
    Univ Arizona, Inst BIO5
    Univ Arizona, Dept Cellular & Mol Med
    Univ Arizona, Dept Immunobiol
    Issue Date
    2016-03-01
    
    Metadata
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    Publisher
    AMER SOC MICROBIOLOGY
    Citation
    Complex Interplay of the UL136 Isoforms Balances Cytomegalovirus Replication and Latency 2016, 7 (2):e01986-15 mBio
    Journal
    mBio
    Rights
    Copyright © 2016 Caviness et al. This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-ShareAlike 3.0 Unported license.
    Collection Information
    This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.
    Abstract
    Human cytomegalovirus (HCMV), a betaherpesvirus, persists indefinitely in the human host through poorly understood mechanisms. The UL136 gene is carried within a genetic locus important to HCMV latency termed the UL133/8 locus, which also carries UL133, UL135, and UL138. Previously, we demonstrated that UL136 is expressed as five protein isoforms ranging from 33-kDa to 19-kDa, arising from alternative transcription and, likely, translation initiation mechanisms. We previously showed that the UL136 isoforms are largely dispensable for virus infection in fibroblasts, a model for productive virus replication. In our current work, UL136 has emerged as a complex regulator of HCMV infection in multiple contexts of infection relevant to HCMV persistence: in an endothelial cell (EC) model of chronic infection, in a CD34(+) hematopoietic progenitor cell (HPC) model of latency, and in an in vivo NOD-scid IL2R gamma(null)(c) humanized (huNSG) mouse model for latency. The 33- and 26-kDa isoforms promote replication, while the 23- and 19-kDa isoforms suppress replication in ECs, in CD34(+) HPCs, and in huNSG mice. The role of the 25-kDa isoform is context dependent and influences the activity of the other isoforms. These isoforms localize throughout the secretory pathway, and loss of the 33- and 26-kDa UL136 isoforms results in virus maturation defects in ECs. This work reveals an intriguing functional interplay between protein isoforms that impacts virus replication, latency, and dissemination, contributing to the overall role of the UL133/8 locus in HCMV infection. IMPORTANCE The persistence of DNA viruses, and particularly of herpesviruses, remains an enigma because we have not completely defined the viral and host factors important to persistence. Human cytomegalovirus, a herpesvirus, persists in the absence of disease in immunocompetent individuals but poses a serious disease threat to transplant patients and the developing fetus. There is no vaccine, and current therapies do not target latent reservoirs. In an effort to define the viral factors important to persistence, we have studied viral genes with no known viral replication function in contexts important to HCMV persistence. Using models relevant to viral persistence, we demonstrate opposing roles of protein isoforms encoded by the UL136 gene in regulating latent and replicative states of infection. Our findings reveal an intriguing interplay between UL136 protein isoforms and define UL136 as an important regulator of HCMV persistence.
    Note
    Open access.
    ISSN
    2150-7511
    DOI
    10.1128/mBio.01986-15
    Version
    Final published version
    Sponsors
    HHS \ NIH \ National Institute of Allergy and Infectious Diseases (NIAID) [AI079059, AI21640]
    Additional Links
    http://mbio.asm.org/lookup/doi/10.1128/mBio.01986-15
    ae974a485f413a2113503eed53cd6c53
    10.1128/mBio.01986-15
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