Herpesvirus Entry into Host Cells Mediated by Endosomal Low pH

Abstract

Herpesviral pathogenesis stems from infection of multiple cell types including the site of latency and cells that support lytic replication. Herpesviruses utilize distinct cellular pathways, including low pH endocytic pathways, to enter different pathophysiologically relevant target cells. This review details the impact of the mildly acidic milieu of endosomes on the entry of herpesviruses, with particular emphasis on herpes simplex virus 1 (HSV-1). Epithelial cells, the portal of primary HSV-1 infection, support entry via low pH endocytosis mechanisms. Mildly acidic pH triggers reversible conformational changes in the HSV-1 class III fusion protein glycoprotein B (gB). In vitro treatment of herpes simplex virions with a similar pH range inactivates infectivity, likely by prematurely activating the viral entry machinery in the absence of a target membrane. How a given herpesvirus mediates both low pH and pH-independent entry events is a key unresolved question.

Keywords: endocytosis; endosomes; gB; herpes simplex viruses; herpesviruses; low pH; viral entry.

Figure 1

Effect of low pH on the antigenic structure of HSV-1 gB (A) gB ectodomain trimer representing a post-fusion conformation. (B) Location of monoclonal antibody binding sites. Monoclonal antibody-resistant mutations in Domain I, which contains bipartite hydrophobic fusion loops, map to amino acid residue 303 for H126 and residues 203, 335 and 199 for SS55 (108, 109). MAb H1359 to Domain III maps approximately to 487–505 (110). The MAb SS10 epitope in Domain IV maps to 640–670 based on binding to fragments and peptides (111). MAbs SS106 and SS144 to Domain V both bind to a 697–725 peptide (71). The oligomer-specific MAb DL16 binds to Domain V as determined by electron microscopy (109). The MAb H1817 epitope in Domain VI (not resolved in the structure) maps to 31–43 based on binding to fragments and peptides (111). MAbs that exhibit reduced reactivity with pre-fusion gB that has been pre-treated with pH <6.2 are marked with (*). The reactivity of unmarked MAbs is unchanged by low pH pre-treatment (43, 61, 63).