1. CCL2 mobilizes ALIX to facilitate Gag-p6 mediated HIV-1 virion release.
- Author
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Ajasin DO, Rao VR, Wu X, Ramasamy S, Pujato M, Ruiz AP, Fiser A, Bresnick AR, Kalpana GV, and Prasad VR
- Subjects
- Cells, Cultured, Humans, Macrophages virology, Calcium-Binding Proteins metabolism, Cell Cycle Proteins metabolism, Chemokine CCL2 metabolism, Endosomal Sorting Complexes Required for Transport metabolism, HIV-1 growth & development, Host-Pathogen Interactions, Virus Release, gag Gene Products, Human Immunodeficiency Virus metabolism
- 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., Competing Interests: DA, VR, XW, SR, MP, AR, AF, AB, GK, VP No competing interests declared
- Published
- 2019
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