title: High-multiplicity HIV-1 infection and neutralizing antibody evasion mediated by the macrophage-T cell virological synapse.
abstract: Macrophage infection is considered to play an important role in HIV-1 pathogenesis and persistence. Using a primary cell-based coculture model, we show that monocyte-derived macrophages (MDM) efficiently transmit a high-multiplicity HIV-1 infection to autologous CD4(+) T cells through a viral envelope glycoprotein (Env) receptor- and actin-dependent virological synapse (VS), facilitated by interactions between ICAM-1 and LFA-1. Virological synapse (VS)-mediated transmission by MDM results in high levels of T cell HIV-1 integration and is 1 to 2 orders of magnitude more efficient than cell-free infection. This mode of cell-to-cell transmission is broadly susceptible to the activity of CD4 binding site (CD4bs) and glycan or glycopeptide epitope-specific broadly neutralizing monoclonal antibodies (bNMAbs) but shows resistance to bNMAbs targeting the Env gp41 subunit membrane-proximal external region (MPER). These data define for the first time the structure and function of the macrophage-to-T cell VS and have important implications for bNMAb activity in HIV-1 prophylaxis and therapy. IMPORTANCE The ability of HIV-1 to move directly between contacting immune cells allows efficient viral dissemination with the potential to evade antibody attack. Here, we show that HIV-1 spreads from infected macrophages to T cells via a structure called a virological synapse that maintains extended contact between the two cell types, allowing transfer of multiple infectious events to the T cell. This process allows the virus to avoid neutralization by a class of antibody targeting the gp41 subunit of the envelope glycoproteins. These results have implications for viral spread in vivo and the specificities of neutralizing antibody elicited by antibody-based vaccines.
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom.
authors.forename: Christopher J A
authors.initials: CJ
authors.lastname: Duncan
authors.forename: James P
authors.initials: JP
authors.lastname: Williams
authors.forename: Torben
authors.initials: T
authors.lastname: Schiffner
authors.forename: Kathleen
authors.initials: K
authors.lastname: Gärtner
authors.forename: Christina
authors.initials: C
authors.lastname: Ochsenbauer
authors.forename: John
authors.initials: J
authors.lastname: Kappes
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Russell
authors.forename: John
authors.initials: J
authors.lastname: Frater
authors.forename: Quentin J
authors.initials: QJ
authors.lastname: Sattentau
mesh_terms: D000704:Analysis of Variance; D000911:Antibodies, Monoclonal / Q000276:immunology*; D057134:Antibodies, Neutralizing / Q000276:immunology*; D015704:CD4 Antigens / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D017931:DNA Primers / Q000235:genetics; D015700:HIV Envelope Protein gp41 / Q000276:immunology; D015658:HIV Infections / Q000276:immunology / Q000635:transmission*; D057131:Immune Evasion / Q000276:immunology*; D054992:Immunological Synapses / Q000821:virology*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008156:Luciferases; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism; D008264:Macrophages / Q000276:immunology* / Q000821:virology; D018613:Microscopy, Confocal; D009500:Neutralization Tests; D016133:Polymerase Chain Reaction; D059008:Time-Lapse Imaging
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D015704:CD4 Antigens; D017931:DNA Primers; D015700:HIV Envelope Protein gp41; D016169:Lymphocyte Function-Associated Antigen-1; D018799:Intercellular Adhesion Molecule-1; D008156:Luciferases