title: Predominant mode of human immunodeficiency virus transfer between T cells is mediated by sustained Env-dependent neutralization-resistant virological synapses.
abstract: Cell-free human immunodeficiency virus type 1 (HIV-1) can initiate infections, but contact between infected and uninfected T cells can enhance viral spread through intercellular structures called virological synapses (VS). The relative contribution of VS to cell-free viral transfer has not been carefully measured. Using an ultrasensitive, fluorescent virus transfer assay, we estimate that when VS between HIV-expressing Jurkat T cells and primary CD4(+) T cells are formed, cell-associated transfer of virus is 18,000-fold more efficient than uptake of cell-free virus. Furthermore, in contrast to cell-free virus uptake, the VS deposits virus rapidly into focal, trypsin-resistant compartments in target T cells. This massive virus internalization requires Env-CD4 receptor interactions but is resistant to inhibition by patient-derived neutralizing antisera that inhibit homologous cell-free virus. Deleting the Env cytoplasmic tail does not abrogate VS-mediated transfer, but it renders the VS sensitive to neutralizing antibodies, suggesting that the tail limits exposure of VS-neutralizing epitopes on the surface of infected cells. Dynamic live imaging of the VS reveals that HIV-expressing cells are polarized and make sustained, Env-dependent contacts with target cells through uropod-like structures. The polarized T-cell morphology, Env-CD4 coordinated adhesion, and viral transfer from HIV-infected to uninfected cells suggest that VS allows HIV-1 to evade antibody neutralization and to disseminate efficiently. Future studies will discern to what extent this massive viral transfer contributes to productive infection or viral dissemination through the migration of virus-carrying T cells.
authors.affiliation: Department of Medicine, Division of Infectious Diseases, Immunology Institute, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Chen
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Hübner
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Spinelli
authors.forename: Benjamin K
authors.initials: BK
authors.lastname: Chen
mesh_terms: D000914:Antibodies, Viral / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology*; D002448:Cell Adhesion; D003599:Cytoskeleton / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000032:analysis / Q000378:metabolism; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007106:Immune Sera / Q000276:immunology; D019169:Jurkat Cells; D008561:Membrane Fusion; D019713:Receptors, CCR5 / Q000378:metabolism; D017384:Sequence Deletion; D053586:Virus Internalization; D054299:env Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism*; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000032:analysis / Q000378:metabolism
chemical_list: D000914:Antibodies, Viral; D007106:Immune Sera; D019713:Receptors, CCR5; D054299:env Gene Products, Human Immunodeficiency Virus; D054301:gag Gene Products, Human Immunodeficiency Virus; D049452:Green Fluorescent Proteins