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A Conditionally Replicating Human Immunodeficiency Virus in BRG-HIS Mice

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Humanized Mice for HIV Research

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Abstract

Vaccination has been a major advance for health care, allowing eradication or reduction of the incidence and mortality of various infectious diseases. However, there remain important pathogens such as the human immunodeficiency virus (HIV)-1 for which classical vaccination approaches have failed. Deciphering the correlates of protection against HIV-1 remains a significant challenge, and new in vivo tools to investigate them are therefore required. We recently developed a conditionally replicating HIV-1 variant (HIV reverse tetracycline transactivator (rtTA)) that depends on the presence of doxycycline (dox) for its replication. In HIV-rtTA, the Tat–transactivating response (TAR) axis of viral transcription regulation was inactivated by mutations and functionally replaced by elements of the Tet-On system for inducible gene expression . Replication of this drug-controlled HIV strain can be turned on/off at will by addition/withdrawal of dox. HIV-rtTA might be a particularly valuable tool to dissect HIV physiopathology and to study the correlates of vaccine-mediated protection. While extensively characterized in vitro, assessing the in vivo replicative capacity of HIV-rtTA was only possible using a mouse model humanized for the immune system (BALB/c Rag2 −/− IL-2Rγc −IL (BRG) human immune system (HIS) mice), in which we could determine the extent of dox bioavailability in various anatomical locations. In this chapter, we discuss the results obtained so far and potential prospects for such conditional-live-virus strains.

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Authors and Affiliations

  1. Laboratory of Experimental Virology, Department of Medical Microbiology, Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam (AMC-UvA), Meibergdreef 15, 1105, Amsterdam, AZ, The Netherlands

    Mireille Centlivre & Ben Berkhout

  2. Centre d’Immunologie et des Maladies Infectieuses-Paris (CIMI-Paris), INSERM U1135, Sorbonnes Universités, UPMC University Paris 06, UMR_S CR7, 91 Bld de l’Hôpital, 75013, Paris, France

    Mireille Centlivre

  3. Department of Cell Biology and Histology, Center for Immunology Amsterdam (CIA), Academic Medical Center, University of Amsterdam (AMC-UvA), Meibergdreef 15, 1105, AZ, Amsterdam, The Netherlands

    Nicolas Legrand

  4. AXENIS, 28 rue du Docteur Roux, 75015, Paris, France

    Nicolas Legrand

Authors
  1. Mireille Centlivre
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  2. Nicolas Legrand
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  3. Ben Berkhout
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Corresponding author

Correspondence to Ben Berkhout .

Editor information

Editors and Affiliations

  1. Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska, USA

    Larisa Y. Poluektova

  2. Center for AIDS Research, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA

    J. Victor Garcia

  3. Research Center for AIDS Laboratory of Viral Pathogenesis, Kyoto University Institute for Virus Research, Sakyo-ku, Japan

    Yoshio Koyanagi

  4. Division of Hematology, University Hospital Zürich, Zürich, Switzerland

    Markus G. Manz

  5. Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA

    Andrew M. Tager

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Centlivre, M., Legrand, N., Berkhout, B. (2014). A Conditionally Replicating Human Immunodeficiency Virus in BRG-HIS Mice. In: Poluektova, L., Garcia, J., Koyanagi, Y., Manz, M., Tager, A. (eds) Humanized Mice for HIV Research. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-1655-9_35

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