Molecular Basis for the Recognition of Herpes Simplex Virus Type 1 Infection by Human Natural Killer Cells

Abstract

Primary infection with Herpes simplex virus type 1 (HSV1) is subclinical or only mildly symptomatic in normal individuals, yet the reason for the body's effective immune defense against this pathogen in the absence of antigen-specific immunity has not been well understood. It is clear that human natural killer (NK) cells recognize and kill HSV1-infected cells, and those individuals who either lack or have functionally impaired NK cells can suffer severe, recurrent, and sometimes fatal HSV1 infection. In this article, we review what is known about the recognition of HSV1 by NK cells, and describe a novel mechanism of innate immune surveillance against certain viral pathogens by NK cells called Fc-bridged cell-mediated cytotoxicity.

Keywords: CD16; IgG; NKG2D; herpes simplex virus type 1; major histocompatibility complex I; natural killer cells.

Figure 1

General rules regulating natural killer (NK) cell activity during herpes simplex virus type 1 (HSV1) infection. NK cells express both inhibitory and activating receptors, which balance activity of NK cells. HSV1 infection could shift the balance by secreting type I interferons, expressing activating ligands, decreasing inhibitory ligands, and engaging antibodies, which collectively lead to activating signals outweighing inhibitory signals. Activated NK cells produce cytokines, express functional proteins, and release granzyme and perforin to kill infected cells.

Figure 2

The role of IgG in modulating natural killer (NK) cell function. (A) An HSV1-specific antibody binds to a specific viral antigen and activates CD16a(+) NK cells through classical antibody-dependent cell-mediated cytotoxicity (ADCC). (B) It has been proposed that antibodies directed against herpes simplex virus type 1 (HSV1) antigens could from a bipolar bridge between a specific viral antigen and the HSV1 IgGFc-binding glycoprotein glycoprotein E (gE), thereby preventing ADCC (64). (C) Endocytosis of viral antigens mediated by the hypothetical antibody bipolar bridge. (D) During primary HSV1 infection, non-immune IgG dominates while a primary immune response is being generated. In this setting, non-immune IgG can directly bind gE via its interface with the CH2–CH3 region of IgG. (E) gE-specific antibody can bind gE via its IgG Fab and prevent gE from binding another IgG at its CH2–CH3 region. (F) HSV1 infection produces large amounts of viral antigens of which gE accounts for only a small fraction. Thus, only a small fraction of the total HSV1-specific IgG can potentially form the bipolar bridge on the HSV1-infected cell.

Figure 3

Structural basis for Fc-bridged cell-mediated cytotoxicity (FcBCC). (A) Model structure of gE-IgG1Fc-CD16a ternary complex showing the non-overlaping binding of herpes simplex virus type 1 (HSV1) glycoprotein E (gE) and CD16a to IgGFc. CD16a is shown as magenta, gE is shown as blue, two monomers of IgGFc dimer are shown as green and lime. (B) A new type of IgG-mediated natural killer (NK) cell activation called FcBCC is shown. IgGFc molecules bound by gE are still accessible for CD16a and able to cluster CD3ζ, thereby activating NK cells to kill HSV1-infected targets prior to the development of a antibody-specific immune response.