Distinct NK Cell Genetic Variants Are Associated With HSV-2 Versus VZV Infection of the CNS

Human alphaherpesvirus infections may cause life-threatening CNS disease. As NK cell responses are crucial for herpesvirus control, we assessed if specific human genetic variants with influence on host NK cell functions are associated with HSV-2 or VZV CNS disease development. We included patients with confirmed CNS disease due to HSV-2 (n = 25) and VZV infection (n = 39), and compared them to 400 population controls. The NK cell-related human genetic variants HLA-E*0101/0103, rs9916629 C/T, NKG2C wt/del, FcγRIIIa 158-F/V were assessed in all cohorts. HLA-E-binding peptide sequences were assessed in the HSV-2 and VZV reference sequences by NCBI BLAST and peptide prediction. In patients with HSV-2-related CNS disease, we observed a significantly increased frequency of the rs9916629 CC variant (32%) and the NKG2C del/del genotype (12%) compared to controls (8% and 1%; p = < 0.0001 and p = 0.0006, respectively), and these variants were identified as independent risk factors for HSV-2 CNS disease. In contrast, VZV CNS patients showed a higher prevalence of the FcγRIIIa 158-F/F variant (59%) than controls (34%; p = 0.006). Our results indicate that distinct NK cell pathways are affected in HSV-2 and VZV CNS disease, respectively, and hint towards differences in genetic predispositions to HSV-2 versus VZV CNS infection.