NTB-A and 2B4 Natural Killer Cell Receptors Modulate the Capacity of a Cocktail of Non-Neutralizing Antibodies and a Small CD4-Mimetic to Eliminate HIV-1-Infected Cells by Antibody-Dependent Cellular Cytotoxicity

Viruses. 2024 Jul 20;16(7):1167. doi: 10.3390/v16071167.

Abstract

Natural Killer (NK) cells have the potential to eliminate HIV-1-infected cells by antibody-dependent cellular cytotoxicity (ADCC). NK cell activation is tightly regulated by the engagement of its inhibitory and activating receptors. The activating receptor CD16 drives ADCC upon binding to the Fc portion of antibodies; NK cell activation is further sustained by the co-engagement of activating receptors NTB-A and 2B4. During HIV-1 infection, Nef and Vpu accessory proteins contribute to ADCC escape by downregulating the ligands of NTB-A and 2B4. HIV-1 also evades ADCC by keeping its envelope glycoproteins (Env) in a "closed" conformation which effectively masks epitopes recognized by non-neutralizing antibodies (nnAbs) which are abundant in the plasma of people living with HIV. To achieve this, the virus uses its accessory proteins Nef and Vpu to downregulate the CD4 receptor, which otherwise interacts with Env and exposes the epitopes recognized by nnAbs. Small CD4-mimetic compounds (CD4mc) have the capacity to expose these epitopes, thus sensitizing infected cells to ADCC. Given the central role of NK cell co-activating receptors NTB-A and 2B4 in Fc-effector functions, we studied their contribution to CD4mc-mediated ADCC. Despite the fact that their ligands are partially downregulated by HIV-1, we found that both co-activating receptors significantly contribute to CD4mc sensitization of HIV-1-infected cells to ADCC.

Keywords: ADCC; CD4 mimetics; NK cell activating receptors; nnAbs; plasma from PLWH.

MeSH terms

  • Antibodies, Neutralizing / immunology
  • Antibody-Dependent Cell Cytotoxicity* / immunology
  • CD4 Antigens / immunology
  • CD4 Antigens / metabolism
  • HIV Antibodies* / immunology
  • HIV Infections* / immunology
  • HIV Infections* / virology
  • HIV-1* / immunology
  • Human Immunodeficiency Virus Proteins / immunology
  • Human Immunodeficiency Virus Proteins / metabolism
  • Humans
  • Killer Cells, Natural* / immunology
  • Signaling Lymphocytic Activation Molecule Family* / immunology
  • Signaling Lymphocytic Activation Molecule Family* / metabolism
  • Viral Regulatory and Accessory Proteins / genetics
  • Viral Regulatory and Accessory Proteins / immunology
  • Viral Regulatory and Accessory Proteins / metabolism
  • Viroporin Proteins
  • nef Gene Products, Human Immunodeficiency Virus / immunology
  • nef Gene Products, Human Immunodeficiency Virus / metabolism

Substances

  • HIV Antibodies
  • Signaling Lymphocytic Activation Molecule Family
  • CD244 protein, human
  • CD4 Antigens
  • Human Immunodeficiency Virus Proteins
  • nef Gene Products, Human Immunodeficiency Virus
  • vpu protein, Human immunodeficiency virus 1
  • Viral Regulatory and Accessory Proteins
  • Antibodies, Neutralizing
  • Viroporin Proteins

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