title: Transmembrane domain membrane proximal external region but not surface unit-directed broadly neutralizing HIV-1 antibodies can restrict dendritic cell-mediated HIV-1 trans-infection.
abstract: BACKGROUND
  Although broadly neutralizing antibodies (bNAbs) have been shown to block a diverse array of cell-free human immunodeficiency type 1 (HIV-1) infections, it remains unclear whether these antibodies exhibit similar potency against mature dendritic cell (mDC)-mediated HIV-1 trans-infection.
  
  
  METHODS
  Sensitivity to bNAbs targeting HIV-1 envelope surface unit gp120 (VRCO1, PG16, b12, and 2G12) and transmembrane domain gp41 (4E10 and 2F5) was examined for both cell-free and mDC-mediated infections of TZM-bl and CD4(+) T cells.
  
  
  RESULTS
  Compared with cell-free infection, mDC-mediated infection was significantly less susceptible to gp120-directed bNAbs for the majority of virus isolates. A b12 antigen-binding fragment blocked both cell-free and mDC-mediated infection with equal efficiency. In contrast, cell-free and mDC-associated viruses were equally sensitive to gp41-directed bNAbs. Anti-gp41 bNAbs bound to the surface of mDCs and localized at the mDC-T cell synaptic junctions in the absence of virus.
  
  
  CONCLUSIONS
  Anti-gp41 bNAbs have the potential to inhibit mDC-mediated HIV-1 infection because they bind plasma membranes prior to the formation of an infectious synapse, positioning them to neutralize subsequent virus transfer. As opposed to gp120-directed antibodies, anti-gp41 bNAbs might prevent HIV-1 infection if transmission or spread at the initial site of invasion occurs from a DC-associated source.
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA 02139, USA. msagar@partners.org
authors.forename: Manish
authors.initials: M
authors.lastname: Sagar
authors.forename: Hisashi
authors.initials: H
authors.lastname: Akiyama
authors.forename: Behzad
authors.initials: B
authors.lastname: Etemad
authors.forename: Nora
authors.initials: N
authors.lastname: Ramirez
authors.forename: Ines
authors.initials: I
authors.lastname: Freitas
authors.forename: Suryaram
authors.initials: S
authors.lastname: Gummuluru
mesh_terms: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing / Q000097:blood*; D015496:CD4-Positive T-Lymphocytes; D002474:Cell-Free System; D002478:Cells, Cultured; D018920:Coculture Techniques; D003713:Dendritic Cells; D015483:HIV Antibodies / Q000097:blood*; D015699:HIV Envelope Protein gp120 / Q000276:immunology; D015658:HIV Infections / Q000276:immunology* / Q000635:transmission*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D018950:Lipopolysaccharide Receptors; D009000:Monocytes
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D018950:Lipopolysaccharide Receptors; C514793:gp120 protein, Human immunodeficiency virus 1