SARS-CoV-2 Infection Associated with HHV-6A Reactivation and an Inhibitory KIR2DL2/HLA-C1 Immunogenetic Profile

Background: Natural killer (NK) cells play a pivotal role in antiviral immunity by finely tuning their effector functions through the integration of activating and inhibitory signals mediated by killer immunoglobulin-like receptors (KIRs). This dynamic balance is essential for effective viral clearance while preventing excessive immune-mediated tissue damage. Among inhibitory KIRs, KIR2DL2 and its cognate ligand HLA-C1 have been implicated in the regulation of NK cell cytotoxicity and cytokine production, thereby influencing susceptibility to viral infections. We have previously demonstrated that an increased frequency of the KIR2DL2/HLA-C1 genotype is associated with enhanced susceptibility to human herpesvirus (HHV) infections, underscoring the critical role of KIR-mediated NK cell regulation in shaping host–virus interactions. Aim: In the present study, we investigated whether co-infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and human herpesvirus 6 (HHV-6) is associated with the KIR2DL2/HLA-C1 genetic background. Methods: A total of 110 SARS-CoV-2-positive subjects and 109 SARS-CoV-2-negative controls were analyzed for KIR2DL2 and HLA-C1 genotypes, as well as for HHV-6A/B reactivation in plasma samples. Results: SARS-CoV-2-positive individuals exhibited a significantly higher frequency of the KIR2DL2/HLA-C1 haplotype and a concomitant increase in HHV-6A reactivation compared with SARS-CoV-2-negative subjects. Notably, the combined presence of the KIR2DL2/HLA-C1 haplotype and HHV-6A DNAemia was more prevalent among deceased patients and those with comorbidities, particularly cardiovascular diseases. Conclusions: Collectively, these findings suggest that the KIR2DL2/HLA-C1 haplotype may enhance inhibitory NK cell signaling, thereby favoring HHV-6A persistence and contributing to immune dysregulation during SARS-CoV-2 infection. The co-occurrence of KIR2DL2/HLA-C1 and HHV-6A reactivation may thus represent a molecular signature associated with adverse COVID-19 outcomes.