1. Microbiology and Infectious Disease
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Integrase-RNA interactions underscore the critical role of integrase in HIV-1 virion morphogenesis

  1. Jennifer L Elliott
  2. Jenna Eve Eschbach
  3. Pratibha C Koneru
  4. Wen Li
  5. Maritza Puray Chavez
  6. Dana Townsend
  7. Dana Q Lawson
  8. Alan N Engelman
  9. Mamuka Kvaratskhelia
  10. Sebla Bulent Kutluay  Is a corresponding author
  1. Washington University School of Medicine, United States
  2. University of Colorado School of Medicine, United States
  3. Department of Cancer Immunology and Virology, United States
  4. Dana-Farber Cancer Institute, United States
Research Article
  • Cited 5
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Cite this article as: eLife 2020;9:e54311 doi: 10.7554/eLife.54311

Abstract

A number of human immunodeficiency virus 1 integrase (IN) alterations, referred to as class II substitutions, exhibit pleotropic effects during virus replication. However, the underlying mechanism for the class II phenotype is not known. Here we demonstrate that all tested class II IN substitutions compromised IN-RNA binding in virions by one of three distinct mechanisms: i) markedly reducing IN levels thus precluding formation of IN complexes with viral RNA; ii) adversely affecting functional IN multimerization and consequently impairing IN binding to viral RNA; iii) directly compromising IN-RNA interactions without substantially affecting IN levels or functional IN multimerization. Inhibition of IN-RNA interactions resulted in mislocalization of the viral ribonucleoprotein complexes outside the capsid lattice, which led to premature degradation of the viral genome and IN in target cells. Collectively, our studies uncover causal mechanisms for the class II phenotype and highlight an essential role of IN-RNA interactions for accurate virion maturation.

Article and author information

Author details

  1. Jennifer L Elliott

    Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Jenna Eve Eschbach

    Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Pratibha C Koneru

    Division of Infectious Diseases, University of Colorado School of Medicine, Aurora, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3955-4548
  4. Wen Li

    Dana-Farber Cancer Institute, Department of Cancer Immunology and Virology, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Maritza Puray Chavez

    Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Dana Townsend

    Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Dana Q Lawson

    Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Alan N Engelman

    Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Mamuka Kvaratskhelia

    Division of Infectious Diseases, University of Colorado School of Medicine, Aurora, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3800-0033
  10. Sebla Bulent Kutluay

    Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, United States
    For correspondence
    kutluay@wustl.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5549-7032

Funding

National Institutes of Health (GM103297)

  • Sebla Bulent Kutluay

National Institutes of Health (GM122458)

  • Sebla Bulent Kutluay

National Institutes of Health (AI143389)

  • Jennifer L Elliott

National Institutes of Health (AI062520)

  • Mamuka Kvaratskhelia
  • Sebla Bulent Kutluay

National Institutes of Health (AI150472)

  • Mamuka Kvaratskhelia

National Institutes of Health (AI070042)

  • Alan N Engelman

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Viviana Simon, Icahn School of Medicine at Mount Sinai, United States

Publication history

  1. Received: December 10, 2019
  2. Accepted: September 22, 2020
  3. Accepted Manuscript published: September 22, 2020 (version 1)
  4. Version of Record published: November 17, 2020 (version 2)

Copyright

© 2020, Elliott et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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