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

AIDS. 2017 Mar 13;31(5):613-622. doi: 10.1097/QAD.0000000000001380.


Design: 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.

Methods: 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.

Results: 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).

Conclusion: 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.

Keywords: antibody-dependent cellular cytotoxicity; cytotoxicity; HIV/AIDS; natural killer cells; VRC01.

MeSH terms

  • Antibodies, Monoclonal / immunology
  • Antibody-Dependent Cell Cytotoxicity*
  • CD4-Positive T-Lymphocytes / physiology*
  • CD4-Positive T-Lymphocytes / virology*
  • Cells, Cultured
  • Down-Regulation
  • HIV Antibodies / immunology
  • HIV Infections / immunology
  • HIV Infections / pathology*
  • Histocompatibility Antigens Class I / biosynthesis*
  • Humans
  • Interferon-alpha / metabolism*
  • Killer Cells, Natural / immunology*


  • Antibodies, Monoclonal
  • HIV Antibodies
  • Histocompatibility Antigens Class I
  • Interferon-alpha