Viral entry mechanisms: cellular and viral mediators of herpes simplex virus entry

Abstract

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.

Figure 1

HSV virion and its two major modes of entry into cells. Structural components of a typical HSV virion are shown (box). HSV virions can enter into cells via a pH-independent fusion of viral envelope with the plasma membrane (I) or alternatively, via an endocytic pathway that may be phagocytosis-like (II) in terms of the viral uptake. In both pathways HSV particles may initially associate with filopodia-like membrane protrusions via heparan sulfate proteoglycan (HSPG). Unidirectional transport of extracellular particles bound to filopodia (HSV surfing) then brings the particles closer to the cell body for entry via interactions with the cellular receptors including gD receptor and possibly gB receptor. Fusion at the plasma membrane results in the release of the naked viral nucleocapsid in the cytoplasm for transport to the nucleus. Similarly, endocytosis also requires fusion of the enveloped particles with the vesicular membrane for the release of the viral nucleocapsid proximal to the nucleus.

Figure 2

Molecular interactions that facilitate HSV entry. Initial attachment to cells is mediated by interaction between heparan sulfate proteoglycans (HSPGs) with HSV glycoproteins gC and/or gB. Membrane fusion is required for the penetration of viral nucleocapsid and the tegument into the cytoplasm. Interaction between gD, gH-gL and a gD receptor may be sufficient to bring conformational changes within gD to trigger merging of viral and cellular membranes or lipid mixing. However, a fourth glycoprotein, gB, is also required for complete fusion and content mixing, which basically results in the release of the tegument and the nucleocapsid into the cytoplasm. A receptor for gB, PILR-α is also expected to play a role during the fusion process. Its precise role is still emerging and therefore, it is not shown above.

Figure 3

Outline of heparan sulfate (HS) maturation. A number of listed enzymes participate in the modification of the parent chain HS, which is a polymer of repeating disaccharide units containing a glucosamine and a glucuronic acid residue. All possible modifications and their preferred sequences (arrows) are shown.