1. Microbiology and Infectious Disease
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CCL2 mobilizes ALIX to facilitate Gag-p6 mediated HIV-1 virion release

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Cite this article as: eLife 2019;8:e35546 doi: 10.7554/eLife.35546

Abstract

Cellular ESCRT machinery plays pivotal role in HIV-1 budding and release. Extracellular stimuli that modulate HIV-1 egress are currently unknown. We found that CCL2 induced by HIV-1 clade B (HIV-1B) infection of macrophages enhanced virus production, while CCL2 immuno-depletion reversed this effect. Additionally, HIV-1 clade C (HIV-1C) was refractory to CCL2 levels. We show that CCL2-mediated increase in virus production requires Gag late motif LYPX present in HIV-1B, but absent in HIV-1C, and ALIX protein that recruits ESCRT III complex. CCL2 immuno-depletion sequestered ALIX to F-actin structures, while CCL2 addition mobilized it to cytoplasm facilitating Gag-ALIX binding. The LYPX motif improves virus replication and its absence renders the virus less fit. Interestingly, novel variants of HIV-1C with PYRE/PYKE tetrapeptide insertions in Gag-p6 conferred ALIX binding, CCL2-responsiveness and enhanced virus replication. These results, for the first time, indicate that CCL2 mediates ALIX mobilization from F-actin and enhances HIV-1 release and fitness.

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Author details

  1. David O Ajasin

    Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Vasudev R Rao

    Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9435-4023
  3. Xuhong Wu

    Department of Genetics, Albert Einstein College of Medicine, Bronx, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Santhamani Ramasamy

    Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Mario Pujato

    Department of Biochemistry, Albert Einstein College of Medicine, Bronx, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Arthur P Ruiz

    Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Andras Fiser

    Department of Systems and Computational Biology, Albert Einstein College of Medicine, Bronx, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Anne R Bresnick

    Department of Biochemistry, Albert Einstein College of Medicine, Bronx, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Ganjam V Kalpana

    Department of Genetics, Albert Einstein College of Medicine, Bronx, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Vinayaka R Prasad

    Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, United States
    For correspondence
    vinayaka.prasad@einstein.yu.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9461-0189

Funding

National Institutes of Health (R37 AI030861)

  • Vinayaka R Prasad

National Institutes of Health (R01 MH083579)

  • Vinayaka R Prasad

National Institutes of Health (R01 GM112520)

  • Ganjam V Kalpana

National Institutes of Health (T32 AI007501)

  • David O Ajasin

National Institutes of Health (F31 AI127295)

  • David O Ajasin

National Institutes of Health (T32 GM007491)

  • Arthur P Ruiz

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

Reviewing Editor

  1. Wesley I Sundquist, University of Utah School of Medicine, United States

Publication history

  1. Received: January 30, 2018
  2. Accepted: June 6, 2019
  3. Accepted Manuscript published: June 7, 2019 (version 1)

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

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