title: IFN-α augments natural killer-mediated antibody-dependent cellular cytotoxicity of HIV-1-infected autologous CD4+ T cells regardless of major histocompatibility complex class 1 downregulation.
abstract: We have previously shown that IFN-α stimulation augments direct natural killer (NK) cell lysis of autologous CD4 primary T cells infected with certain HIV-1 isolates based upon major histocompatibility complex class 1 (MHC-1) downregulation capacity. Here, we investigated if antibody-dependent cellular cytotoxicity (ADCC) could trigger lysis of HIV-1 isolates that were resistant to direct NK lysis and if IFN-α prestimulation of NK cells could further enhance ADCC.
  
  
  
  Using broadly neutralizing monoclonal antibodies against gp120 (VRC01 or PGV04) or plasma from HIV-1-infected patients (ART-suppressed or elite controller) to trigger ADCC, we measured NK cell chromium release cytotoxicity against HIV-1-infected autologous CD4 primary T cells and NK cell CD107a degranulation against gp120-coated CD4 T cells. Total or NK-depleted peripheral blood mononuclear cells were used as effectors in the presence or absence of IFN-α prestimulation.
  
  
  
  Plasma from HIV-1-infected patients and monoclonal antibodies against gp120 could trigger NK-dependent ADCC lysis of viral isolates that were resistant to direct NK cell lysis following IFN-α stimulation. In contrast, viral isolates that exhibited potent MHC-I downregulation capacity could be lysed by NK cells through either IFN-α stimulated direct cytotoxicity or through ADCC. When utilized in combination, IFN-α prestimulation significantly augmented ADCC lysis of HIV-1-infected target cells and increased NK cell CD107a degranulation against gp120-coated ADCC targets (P < 0.05, n = 6).
  
  
  
  HIV-1 isolates with lower MHC-I downregulation capacity are resistant to direct lysis following IFN-α stimulation but retain sensitivity to ADCC. IFN-α prestimulation can significantly increase NK-mediated clearance of HIV-1-infected target cells by both ADCC and/or direct cytotoxicity depending on MHC downregulation status.
authors.affiliation: HIV Immunopathogenesis Laboratory, The Wistar Institute
authors.forename: Costin
authors.initials: C
authors.lastname: Tomescu
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Pablo
authors.initials: P
authors.lastname: Tebas
authors.affiliation: HIV Immunopathogenesis Laboratory, The Wistar Institute
authors.forename: Luis J
authors.initials: LJ
authors.lastname: Montaner
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology; D000920:Antibody-Dependent Cell Cytotoxicity; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology* / Q000821:virology*; D002478:Cells, Cultured; D015536:Down-Regulation; D015483:HIV Antibodies / Q000276:immunology; D015658:HIV Infections / Q000276:immunology / Q000473:pathology*; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis*; D006801:Humans; D016898:Interferon-alpha / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D015483:HIV Antibodies; D015395:Histocompatibility Antigens Class I; D016898:Interferon-alpha
keywords: antibody-dependent cellular cytotoxicity; cytotoxicity; HIV/AIDS; natural killer cells; VRC01