Natural killer (NK) cell-deficient patients are particularly susceptible to severe
infection with herpesviruses, especially varicella-zoster virus (VZV) and herpes simplex virus 1 (HSV-1). The critical role that NK cells play in controlling these
infections denotes an intricate struggle for dominance between virus and NK cell
antiviral immunity; however, research in this area has remained surprisingly limited. Our study addressed this absence of knowledge and found that
infection with VZV was not associated with enhanced NK cell activation, suggesting that the virus uses specific mechanisms to limit NK cell activity. Analysis of viral regulation of
ligands for NKG2D, a potent activating receptor ubiquitously expressed on NK cells, revealed that VZV differentially modulates expression of the NKG2D
ligands MICA, ULBP2, and ULBP3 by upregulating
MICA expression while reducing ULBP2 and ULBP3 expression on the surface of infected cells. Despite being closely related to VZV,
infection with HSV-1 produced a remarkably different effect on NKG2D
ligand expression. A significant decrease in
MICA, ULBP2, and ULBP3 was observed with HSV-1
infection at a total cellular
protein level, as well as on the cell surface. We also demonstrate that HSV-1 differentially regulates expression of an additional NKG2D
ligand, ULBP1, by reducing cell surface expression while total
protein levels are unchanged. Our findings illustrate both a striking point of difference between two closely related alphaherpesviruses, as well as suggest a powerful capacity for VZV and HSV-1 to evade
antiviral NK cell activity through novel modulation of NKG2D
ligand expression.
IMPORTANCE: Patients with deficiencies in NK cell function experience an extreme susceptibility to
infection with herpesviruses, in particular, VZV and HSV-1. Despite this striking correlation, research into understanding how these two alphaherpesviruses interact with NK cells is surprisingly limited. Through examination of viral regulation of
ligands to the activating
NK cell receptor NKG2D, we reveal patterns of modulation by VZV, which were unexpectedly varied in response to regulation by HSV-1
infection. Our study begins to unravel the undoubtedly complex interactions that occur between NK cells and alphaherpesvirus
infection by providing novel insights into how VZV and HSV-1 manipulate NKG2D
ligand expression to modulate NK cell activity, while also illuminating a distinct variation between two closely related alphaherpesviruses.