Single-cell RNA sequencing reveals distinct immune interaction networks in primary and reactivated HHV-6B infection

Human herpesvirus 6B (HHV-6B) infection causes clinically distinct diseases in primary infection or viral reactivation. Primary infection manifests as exanthem subitum (ES), a common childhood febrile exanthem; whereas reactivation is associated with drug reaction with eosinophilia and systemic symptoms (DRESS), a severe cutaneous adverse reaction. The immune mechanisms underlying these divergent outcomes remain poorly understood.

We performed single-cell RNA sequencing of peripheral blood mononuclear cells from patients with ES and DRESS. Comparative analysis of immune cell populations and transcriptional programs during the acute and recovery phases revealed distinct immune interaction networks.

Primary HHV-6B infection was characterized by marked expansion of proliferating natural killer (NK) cells, which expressed cytotoxic effector genes including GNLY and NKG7. Cell-cell communication analysis predicted strong communication between proliferating NK cells and inflammatory monocytes during acute ES. In contrast, HHV-6B reactivation in DRESS was associated with expansion of proliferating CD4+ T cells with inflammatory transcriptional signatures that showed predicted communication with CD14+ monocytes. Despite these differences, monocytes occupied a prominent position within the predicted interaction networks in both conditions. Complementary protein-level analysis identified CXCL10 as a shared systemic inflammatory marker in active HHV-6B infection.

HHV-6B infection exhibits distinct immune interaction networks depending on the clinical context, characterized by proliferating NK cell-monocyte interactions during primary infection and proliferating CD4+ T cell-monocyte interactions during viral reactivation.