CCL2 mobilizes ALIX to facilitate Gag-p6 mediated HIV-1 virion release

Elife. 2019 Jun 7;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.

Keywords: ALIX; CCL2; Gag p6; HIV-1; HIV-1 clade C; human; infectious disease; late domain; microbiology; virus.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Calcium-Binding Proteins / metabolism*
  • Cell Cycle Proteins / metabolism*
  • Cells, Cultured
  • Chemokine CCL2 / metabolism*
  • Endosomal Sorting Complexes Required for Transport / metabolism*
  • HIV-1 / growth & development*
  • Host-Pathogen Interactions*
  • Humans
  • Macrophages / virology
  • Virus Release*
  • gag Gene Products, Human Immunodeficiency Virus / metabolism*

Substances

  • CCL2 protein, human
  • Calcium-Binding Proteins
  • Cell Cycle Proteins
  • Chemokine CCL2
  • Endosomal Sorting Complexes Required for Transport
  • PDCD6IP protein, human
  • gag Gene Products, Human Immunodeficiency Virus
  • p6 gag protein, Human immunodeficiency virus 1