CCL2 mobilizes ALIX to facilitate Gag-p6 mediated HIV-1 virion release
- Albert Einstein College of Medicine, United States
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.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 1, 2, 3B, 3C, 3E, 4A, 4B, 5B, 6B, 7B, 9A, 9B, 10B, 11B, 11C, 12, S1B, S2A, S2B, S2C, S2D, S3A, S4 and S6
Article and author information
Author details
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
- Wesley I Sundquist, University of Utah School of Medicine, United States
Version history
- Received: January 30, 2018
- Accepted: June 6, 2019
- Accepted Manuscript published: June 7, 2019 (version 1)
- Version of Record published: June 25, 2019 (version 2)
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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CCL2 mobilizes ALIX to facilitate Gag-p6 mediated HIV-1 virion release
eLife 8:e35546.
https://doi.org/10.7554/eLife.35546
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