title: HIV Envelope gp120 Alters T Cell Receptor Mobilization in the Immunological Synapse of Uninfected CD4 T Cells and Augments T Cell Activation.
abstract: HIV is transmitted most efficiently from cell to cell, and productive infection occurs mainly in activated CD4 T cells. It is postulated that HIV exploits immunological synapses formed between CD4 T cells and antigen-presenting cells to facilitate the targeting and infection of activated CD4 T cells. This study sought to evaluate how the presence of the HIV envelope (Env) in the CD4 T cell immunological synapse affects synapse formation and intracellular signaling to impact the downstream T cell activation events. CD4 T cells were applied to supported lipid bilayers that were reconstituted with HIV Env gp120, anti-T cell receptor (anti-TCR) monoclonal antibody, and ICAM-1 to represent the surface of HIV Env-bearing antigen-presenting cells. The results showed that the HIV Env did not disrupt immunological synapse formation. Instead, the HIV Env accumulated with TCR at the center of the synapse, altered the kinetics of TCR recruitment to the synapse and affected synapse morphology over time. The HIV Env also prolonged Lck phosphorylation at the synapse and enhanced TCR-induced CD69 upregulation, interleukin-2 secretion, and proliferation to promote virus infection. These results suggest that HIV uses the immunological synapse as a conduit not only for selective virus transmission to activated CD4 T cells but also for boosting the T cell activation state, thereby increasing its likelihood of undergoing productive replication in targeted CD4 T cells.
  
  
  OBJECTIVE
  There are about two million new HIV infections every year. A better understanding of how HIV is transmitted to susceptible cells is critical to devise effective strategies to prevent HIV infection. Activated CD4 T cells are preferentially infected by HIV, although how this is accomplished is not fully understood. This study examined whether HIV co-opts the normal T cell activation process through the so-called immunological synapse. We found that the HIV envelope is recruited to the center of the immunological synapse together with the T cell receptor and enhances the T cell receptor-induced activation of CD4 T cells. Heightened cellular activation promotes the capacity of CD4 T cells to support productive HIV replication. This study provides evidence of the exploitation of the normal immunological synapse and T cell activation process by HIV to boost the activation state of targeted CD4 T cells and promote the infection of these cells.
authors.affiliation: Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, New York, USA.|Department of Pathology, New York University School of Medicine, New York, New York, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Deng
authors.affiliation: Icahn School of Medicine at Mount Sinai, Division of Infectious Diseases, New York, New York, USA.
authors.forename: Yu-Ya
authors.initials: YY
authors.lastname: Mitsuki
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, New York, USA.
authors.forename: Guomiao
authors.initials: G
authors.lastname: Shen
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Jocelyn C
authors.initials: JC
authors.lastname: Ray
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Claudia
authors.initials: C
authors.lastname: Cicala
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: James
authors.initials: J
authors.lastname: Arthos
authors.affiliation: Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, New York, USA.|Department of Pathology, New York University School of Medicine, New York, New York, USA.|The Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, The University of Oxford, Headington, United Kingdom.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Dustin
authors.affiliation: Icahn School of Medicine at Mount Sinai, Division of Infectious Diseases, New York, New York, USA catarina.hioe@mssm.edu.|James J. Peters Veterans Affairs Medical Center, Research Service, Bronx, New York, USA.
authors.forename: Catarina E
authors.initials: CE
authors.lastname: Hioe
mesh_terms: D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology; D006678:HIV / Q000276:immunology / Q000502:physiology; D015483:HIV Antibodies / Q000008:administration & dosage; D015699:HIV Envelope Protein gp120 / Q000037:antagonists & inhibitors / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology / Q000635:transmission / Q000821:virology; D006801:Humans; D054992:Immunological Synapses / Q000378:metabolism*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008051:Lipid Bilayers; D008213:Lymphocyte Activation; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015398:Signal Transduction; D014779:Virus Replication
chemical_list: D000911:Antibodies, Monoclonal; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; C573420:ICAM1 protein, human; D008051:Lipid Bilayers; D011948:Receptors, Antigen, T-Cell; D018799:Intercellular Adhesion Molecule-1; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)