Novel therapeutic investigational strategies to treat severe and disseminated HSV infections suggested by a deeper understanding of in vitro virus entry processes

•HSV-1 and 2 infections have a huge global impact.•Current anti-HSV therapies are burdened by several important limitations.•No clear consensus exists on molecular events leading to HSV infection.•Study of HSV entry and transmission is fundamental to identify proper drug targets.•Anti-HSV Hu-mAbs can fill the gaps of current therapies and address vaccine design.

The global burden of herpes simplex virus (HSV) legitimates the critical need to develop new prevention strategies, such as drugs and vaccines that are able to fight either primary HSV infections or reactivations. Moreover, the ever-growing number of patients receiving transplants increases the number of severe HSV infections that are unresponsive to current therapies. Finally, the high global incidence of genital HSV-2 infection increases the risk of perinatal transmission to newborns, in which disseminated infection or central nervous system (CNS) involvement is frequent, with associated high morbidity and mortality rates. There are several key features shared by novel anti-HSV drugs, from currently available optimized drugs to small molecules able to interfere with various virus replication steps. However, several virological aspects of the disease and associated clinical needs highlight why an ideal anti-HSV drug has yet to be developed.