@article{f304091598434693a7f5254acc40d1d8,
title = "CCL2 mobilizes ALIX to facilitate Gag-p6 mediated HIV-1 virion release",
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 immunodepletion 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 immunodepletion 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.",
author = "Ajasin, {David O.} and Rao, {Vasudev R.} and Xuhong Wu and Santhamani Ramasamy and Mario Pujato and Ruiz, {Arthur P.} and Andras Fiser and Bresnick, {Anne R.} and Kalpana, {Ganjam V.} and Prasad, {Vinayaka R.}",
note = "Funding Information: 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. Funding Information: The authors wish to acknowledge Duncan Wilson for many useful discussions, Kartik Chandran and Kimberly Merani for reading the manuscript, Eitan Novogrodsky for technical assistance, the Einstein-Rockefeller-CUNY Center for AIDS Research (ERC-CFAR) (P30 AI051519) for the use of core facilities and Dr. Eliseo Eugenin for the use of confocal microscope at Rutgers University in our initial studies. The authors would like to acknowledge the Analytical Imaging Facility (AIF) for assistance with microscopy: Hillary Guzik for assistance with the confocal microscope (Leica SP8 was funded by Shared Instrumentation Grant 1S100D023591-01) and figures and Timothy Mendez for assistance with the electron microscopy (JEOL JEM-1400Plus was funded by a Shared Instrumentation Grant 1S10OD016214-01A1). The AIF is funded in part by the National Cancer Institute Cancer Grant P30CA013330. The work reported here was supported by NIH grants R37 AI030861 and R01 MH083579 (to VRP) and R01 GM112520 (to GVK). DOA acknowledges support from the institutional HIV/AIDS training grant NIH T32 AI007501 and F31 AI127295. The authors declare that they have no conflicts of interest. Publisher Copyright: {\textcopyright} 2019, eLife Sciences Publications Ltd. All rights reserved.",
year = "2019",
month = jun,
doi = "10.7554/eLife.35546",
language = "English (US)",
volume = "8",
journal = "eLife",
issn = "2050-084X",
publisher = "eLife Sciences Publications",
}
