title: CCR5 interaction with HIV-1 Env contributes to Env-induced depletion of CD4 T cells in vitro and in vivo.
abstract: BACKGROUND
  CD4 T cell depletion during HIV-1 infection is associated with AIDS disease progression, and the HIV-1 Env protein plays an important role in the process. Together with CXCR4, CCR5 is one of the two co-receptors that interact with Env during virus entry, but the role of CCR5 in Env-induced pathogenesis is not clearly defined. We have investigated CD4 T cell depletion mechanisms caused by the Env of a highly pathogenic CXCR4/CCR5 dual-tropic HIV-1 isolate R3A.
  
  
  RESULTS
  We report here that R3A infection induced depletion of both infected and uninfected "bystander" CD4 T cells, and treatment with CCR5 antagonist TAK-779 inhibited R3A-induced bystander CD4 T cell depletion without affecting virus replication. To further define the role of Env-CCR5 interaction, we utilized an Env-mutant of R3A, termed R3A-5/6AA, which has lost CCR5 binding capability. Importantly, R3A-5/6AA replicated to the same level as wild type R3A by using CXCR4 for viral infection. We found the loss of CCR5 interaction resulted in a significant reduction of bystander CD4 T cells death during R3A-5/6AA infection, whereas stimulation of CCR5 with MIP1-β increased bystander pathogenesis induced by R3A-5/6AA. We confirmed our findings using a humanized mouse model, where we observed similarly reduced pathogenicity of the mutant R3A-5/6AA in various lymphoid organs in vivo.
  
  
  CONCLUSIONS
  We provide the first evidence that shows CCR5 interaction with a dual-tropic HIV-1 Env played a significant role in Env-induced depletion of CD4 T cells.
authors.affiliation: Curriculum of Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.|Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Li-Chung
authors.initials: LC
authors.lastname: Tsao
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Haitao
authors.initials: H
authors.lastname: Guo
authors.affiliation: Curriculum of Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Jerry
authors.initials: J
authors.lastname: Jeffrey
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: James A
authors.initials: JA
authors.lastname: Hoxie
authors.affiliation: Curriculum of Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. lsu@med.unc.edu.|Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. lsu@med.unc.edu.|Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. lsu@med.unc.edu.
authors.forename: Lishan
authors.identifier: http://orcid.org/0000-0001-6525-3146
authors.initials: L
authors.lastname: Su
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology*; D002478:Cells, Cultured; D015497:HIV-1 / Q000502:physiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D016513:Mice, SCID; D019713:Receptors, CCR5 / Q000378:metabolism*; D054299:env Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
chemical_list: C584933:CCR5 protein, human; D019713:Receptors, CCR5; D054299:env Gene Products, Human Immunodeficiency Virus
keywords: Bystander CD4 T cells; CCR5; HIV-1 Env; HIV-1 pathogenesis; Humanized mice