Herpes simplex virus type‐1 and type‐2 are highly prevalent human pathogens causing life‐long infections. The process of infection begins when the virions bind heparan sulfate moieties present on host cell surfaces. This initial attachment then triggers a cascade of molecular interactions involving multiple viral and host cell proteins and receptors, leading to penetration of the viral nucleocapsid and tegument proteins into the cytoplasm. The nucleocapsid is then transported to the nuclear membrane and the viral DNA is released for replication in the nucleus. Recent studies have revealed that herpes simplex virus entry or penetration into cells may be a highly complex process and the mechanism of entry may demonstrate unique cell‐type specificities. Although specificities clearly exist, past and ongoing studies demonstrate that herpes simplex virus may share certain common receptors and pathways that are also used by many other human viruses. This minireview helps to shed light on recent revelations on the herpes simplex virus entry process.

It is becoming increasingly clear that herpesviruses can exploit the endocytic pathway to infect cells, yet several important features of this process remain poorly defined. Using herpes simplex virus-1 (HSV-1) as a model, we demonstrate that endocytosis of the virions mimic many features of phagocytosis. During entry, HSV-1 virions associated with plasma membrane protrusions followed by a phagocytosis-like uptake involving rearrangement of actin cytoskeleton and trafficking of the virions in large phagosome-like vesicles. RhoA GTPase was activated during this process and the mode of entry was cell type–specific. Clathrin-coated vesicles had no detectable role in virion trafficking as Eps15 dominant-negative mutants failed to affect HSV-1 uptake. Binding and fusion of the virion envelope with the phagosomal membrane is likely facilitated by clustering of nectin-1 (or HVEM) in phagosomes, which was observed in infected cells. Collectively, our data suggests a novel mode of uptake by which the virus can infect both professional and nonprofessional phagocytes.