Entry of Herpes Simplex Virus Type 1 into Cells — Early Steps in Virus Pathogenicity

Abstract

SummaryThe entry of herpes simplex virus type 1 (HSV-1) virions into cells represents the initial stage in the process by which HSV-1 introduces its genetic information into a living cell. The molecular basis of virus entry into cells is the ability of the virion’s structural proteins to recognize and interact with protein components of the cell membrane serving as virus receptors. Electron microscopic studies of the cell-associated virions revealed that many virions bind to the cell membrane, but some virions bind to pits in the cell membrane which are either uncoated or clathrincoated pits (Rosenthal et al. 1984). The virions that bind to the cell membrane enter the cell cytoplasm by a fusion mechanism, while the virions attached to the membrane pits enter the cell cytoplasm by the endocytosis mechanism.In the present chapter, several aspects of HSV-1 entry into cells is discussed, based on reported studies and on studies performed by us. A comprehensive analysis is presented of the molecular mechanisms involved in HSV-1 entry by fusion of virion envelopes with the cell membrane and by entry through coated pits by an endocytosis process. The interaction of HSV-1 virions with the heparan sulfate moiety on the proteoglycans present in the cell membrane was reported (WuDunn and Spear 1989). In the present study, results showing a markedly reduced adsorption of HSV-1 virions to a Chinese hamster ovary (CHO) mutant in the synthesis of heparan sulfate are presented, together with evidence that a specific amino acid sequence in HSV-1 glycoprotein B (gB) — and similar sequences in HSV-1 gC and gH — are responsible for the virion’s attachment to heparan sulfate. A synthetic peptide which contains ten amino acids of the above domain of HSV-1 gB interferes with HSV-1 infection of cells. It is also suggested that the N terminus of the virion’s gD polypeptide contains a fusion sequence which enters the cell membrane and causes its destabilization (Rosenthal et al.1984). The fusion of the virion envelope with the cell membrane is then possible, leading to uncoating of the virion and transport of the viral capsid through the cytoplasm, thus releasing the viral DNA into the nucleus to allow viral gene expression. The effects of inhibitors of enzymatic activities in the cell membrane (quercetin, amiloride, neomycin) on virus infection are discussed.It is suggested that the interaction of HSV-1 virions with coated pits occurs either after binding of virions to heparan sulfate on cellular proteoglycans or directly with the proteins present in coated pits on the cell membrane. The amino acid sequence in HSV-1 gB, which binds to heparan sulfate, was shown to resemble the amino acid sequence in apolipoprotein E (apoE), which itself has been shown to interact with the low-density lipid receptor (LDLR) in coated pits (Dyer and Curtiss 1991). We suggest that HSV-1 may have the ability to interact with LDLR in coated pits due to the interaction of domains in gB, gC, or gD that resemble the apoE attachment sequence to LDLR. Like LDL, HSV-1 virions are incorporated into the cell cytoplasm by an endocytosis process. The fate of virions entering cells by endocytosis seems to differ from the fate of virions entering the cells by fusion. The significance of endocytosis in the penetration of HSV-1 virions into cells through coated pits in the cell membrane is not yet known and requires special attention.