We investigated the presence and replicative state of HHV-6A and 6B in SSc patients both at the blood and tissue level, the immune responses against the virus (focusing in particular on antibody and NK response), the host KIR type and HLA-G expression, and, as a proof of concept of HHV-6A and 6B involvement in fibrosis induction, the ability of HHV-6A/B infection to induce an aberrant expression of pro-fibrotic factors in vascular endothelial cells. This evidence concerns the gene HLA-G and systemic sclerosis.