Abstract
BACKGROUND: Chronic norovirus infection (CNI) causes significant morbidity in immunocompromised patients. No effective prevention or treatment currently exists. METHODS: Two patients with inborn errors of immunity, X-linked severe combined immunodeficiency (X-SCID) and DOCK8 deficiency, were followed longitudinally for clinical course, immune reconstitution, norovirus-specific T-cell (NST) response, B-cell reconstitution, and norovirus-specific antibody production. Samples were obtained in the peri-hematopoietic stem cell transplant (HSCT) setting before and after CNI clearance. The norovirus strain causing CNI was followed longitudinally for norovirus stool viral loads and sequencing. RESULTS: The noroviruses were identified as GII.4 Sydney[P4 New Orleans] in 1 patient and GII.17[P17] in the other. An exacerbation of diarrhea post-HSCT in the patient with X-SCID was consistent with norovirus infection but not with graft-versus-host disease on pathologic samples. Both patients recovered polyfunctional NSTs in the CD4 and CD8 T-cell compartments that recognized multiple norovirus structural and nonstructural viral antigens. T-cell responses were minimal during active CNI but detectable after resolution. Mapping of NST responses between the patient with DOCK8 deficiency and his matched sibling donor were nearly identical. B-cell reconstitution or new endogenous antibody production for immunoglobulin A or immunoglobulin G was not observed. CONCLUSIONS: This report is the first to demonstrate reconstitution of NST immunity after HSCT closely temporally aligned with clearance of CNI, suggesting that cellular immunity is sufficient for norovirus clearance.