The Immunologic Basis for Severe Neonatal Herpes Disease and Potential Strategies for Therapeutic Intervention

Table 2

Potential interventions targeting host defenses against neonatal HSV infection.

Potential intervention	Comments
Maternal vaccination	No effective HSV vaccine is yet available. Neonatal HSV infection could be prevented by a vaccine that either conferred sterilizing immunity to women prior to pregnancy and/or by modifying infection in women to reduce viral replication and shedding in the genital mucosa [63].
Antimicrobial peptides	AMPs formulated as a vaginal microbicide might prevent HSV infection during pregnancy and/or reduce intrapartum transmission [64].
Immunosuppressive therapy for CNS infection	Some component of the immune response to HSV encephalitis may result in pathologic inflammation and contribute to poor outcomes [65–67]. Despite case reports of good outcomes using adjunctive corticosteroids in adults or neonates with HSV CNS infection [68–70], no controlled studies have been performed and this or other immunosuppressive treatments cannot currently be recommended given the risks of increased viral replication and cytotoxic effects.
Immunomodulation of neonatal Th2/Th17 bias	Th1-type responses might be promoted during the neonatal period with novel adjuvants such as imazoquinolines [47, 48], growth factors such as Flt3-L [71], or other agents that target antigen-presenting cells. These strategies might conceivably be used therapeutically during infection or to prime all neonates to respond to infection and vaccinations [48].
Inhibition of suppressor cell function	Tregs, MDSCs, or other suppressor cell populations might contribute to impaired T cell responses during early infancy. Modulation of these cells’ activity might improve immunity to HSV infection, such as what has been proposed for HIV and cancer [72–74]. Inhibition of suppressor cell function during HSV infection might also result in uncontrolled inflammation and worse outcomes [75].
Induction of autophagy	Novel antivirals have been proposed to target HSV virulence factors that inhibit autophagy [76], and early studies suggest that agents that induce autophagy can inhibit HSV replication. Nelfinavir and pentagalloylglucose both induce autophagy and inhibit HSV replication in vitro [77, 78].