Glycoprotein B from strain 17 of herpes simplex virus type I contains an invariant chain homologous sequence that binds to MHC class II molecules.

Major histocompatibility complex class I (MHCI) molecules are major targets of virus evasion strategies because they introduce antigens from the biosynthesis pathway into the antigen-processing and presentation pathways for immune recognition by CD8+ T cells. Little is known about viral strategies that interfere with the MHC class II (MHCII) antigen presentation pathway. We identified a six amino acid sequence from type I herpes simplex virus (HSV-1) glycoprotein B (gB) that is identical to a sequence of human leucocyte antigen D (HLA-D) -associated invariant chain (Ii). In addition, this gB sequence is adjacent to a highly conserved HLA-DR1 binding motif. Both viral sequences together resemble the class II binding site of human Ii, consisting of a MHCII groove binding segment and a promiscuous binding site. We cloned gB from HSV-1 strain 17 and demonstrate association of the virus envelope protein to three HLA-DR allotypes. With chimeric Ii/gB fusion proteins we identified gB sequences that mediate promiscuous or allotype-specific binding to the HLA-DR peptide-binding domain. Mutation of two Lys residues in the viral segment of Ii/gB abolished promiscuous binding to HLA-DR heterodimers. The result indicates promiscuous binding of the virus sequence to HLA-DR molecules and suggests a potential for HSV-1 to manipulate antigen processing and presentation.