US6 Gene Deletion in Herpes Simplex Virus Type 2 Enhances Dendritic Cell Function and T Cell Activation

Herpes simplex virus (HSV) type 1 (HSV-1) and type 2 (HSV-2) produce lifelong infections that are associated with frequent asymptomatic or clinically apparent reactivation. Importantly, HSV express multiple virulence factors that negatively modulate innate and adaptive immune components. Notably, HSV interfere with dendritic cell (DC) viability and function, likely hindering the capacity of the host to mount effective immunity against these viruses. Recently, an HSV-2 virus that was deleted in glycoprotein D was engineered (designated triangle gD-2). The virus is propagated on a complementing cell line that expresses HSV-1 gD, which permits a single round of viral replication. triangle gD-2 is safe, immunogenic, and provided complete protection against vaginal or skin challenges with HSV-1 and HSV-2 in murine models. Here, we sought to assess the interaction of AgD-2 with DCs and found that, in contrast to wild-type (WT) virus which induces DC apoptosis, AgD-2 promoted their migration and capacity to activate naive CD8(+) and CD4(+) T cells in vitro and in vivo. Furthermore, DCs exposed to the WT and triangle gD-2 virus experienced different unfolded protein responses. Mice primed with DCs infected with triangle gD-2 in vitro displayed significantly reduced infection and pathology after genital challenge with virulent HSV-2 compared to non-primed mice, suggesting that DCs play a role in the immune response to the vaccine strain.