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Principles for studying in vivo attenuation of virus mutants: defining the role of the cytomegalovirus gH/gL/gO complex as a paradigm

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Abstract

Initial virus entry into cells of host organs and subsequent spread of viral progeny between tissue cells are events fundamental to viral pathogenesis. Glycoprotein complexes inserted in the virion envelope are critically involved in the cell entry process. Here we review and discuss recent work that has shed light on the in vivo role of the trimeric glycoprotein complex gH/gL/gO of murine cytomegalovirus (mCMV) as a model to propose the role of the corresponding complex of human CMV, for which experimental studies in vivo are not feasible due to the host species specificity of CMVs and evident ethical constraints. A novel approach combining gO transcomplementation of a genetically gO-deficient virus and a mathematical log-linear regression analysis of the viral multiplication kinetics in host tissues revealed a critical role of mCMV gH/gL/gO only in first target cell entry of virions arriving with the circulation, whereas intra-tissue spread proceeded unaffected also in the absence of gH/gL/gO. These findings predict that targeting gO for an antiviral intervention may be of prophylactic value in preventing the seeding of virus to organs, but will likely fail to interfere with an established primary organ infection or with recurrent infection after virus reactivation from latency within tissue cells. The demonstration in the murine model of alternative gH/gL complexes gH/gL/gO and gH/gL/MCK-2, substituting one another in a redundant fashion for securing viral spread in tissues, has the medically interesting bearing that targeting the gH/gL core complex directly may be a promising approach to preventing primary, established, and recurrent CMV infections.

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Acknowledgments

This work was supported by the Deutsche Forschungsgemeinschaft through grant AD131/3-2 (BA) and the Clinical Research Group KFO 183 (NAWL and MJR). NAWL received intramural funding from the young investigator program MAIFOR of the University Medical Center Mainz.

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Authors and Affiliations

  1. Institute for Virology, University Medical Center of the Johannes Gutenberg-University Mainz and Research Center for Immunotherapy (FZI), Obere Zahlbacher Strasse 67, Hochhaus am Augustusplatz, 55131, Mainz, Germany

    Jürgen Podlech, Matthias J. Reddehase & Niels A. W. Lemmermann

  2. Max von Pettenkofer-Institute for Virology, Ludwig-Maximilians-University Munich, Pettenkoferstraße 9A, 80336, Munich, Germany

    Barbara Adler

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  1. Jürgen Podlech
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  2. Matthias J. Reddehase
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  3. Barbara Adler
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  4. Niels A. W. Lemmermann
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Correspondence to Niels A. W. Lemmermann.

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B. Adler and N. A. W. Lemmermann are co-senior authors.

This article is part of the Special Issue on Cytomegalovirus.

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Podlech, J., Reddehase, M.J., Adler, B. et al. Principles for studying in vivo attenuation of virus mutants: defining the role of the cytomegalovirus gH/gL/gO complex as a paradigm. Med Microbiol Immunol 204, 295–305 (2015). https://doi.org/10.1007/s00430-015-0405-2

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