TY - JOUR TI - CCL2 mobilizes ALIX to facilitate Gag-p6 mediated HIV-1 virion release AU - Ajasin, David O AU - Rao, Vasudev R AU - Wu, Xuhong AU - Ramasamy, Santhamani AU - Pujato, Mario AU - Ruiz, Arthur P AU - Fiser, Andras AU - Bresnick, Anne R AU - Kalpana, Ganjam V AU - Prasad, Vinayaka R A2 - Sundquist, Wesley I A2 - Kuriyan, John VL - 8 PY - 2019 DA - 2019/06/07 SP - e35546 C1 - eLife 2019;8:e35546 DO - 10.7554/eLife.35546 UR - https://doi.org/10.7554/eLife.35546 AB - 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. KW - CCL2 KW - ALIX KW - HIV-1 KW - HIV-1 clade C KW - Gag p6 KW - late domain JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -