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.