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. 2021 Mar 4;10(3):542. doi: 10.3390/cells10030542

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© 2021 by the authors.

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).

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Mechanisms used by human herpesviruses to enter host cells. (A) Clathrin-mediated entry for herpesviruses in general. Herpesviruses induce clathrin oligomerization, together with the recruitment of host factors and adapter proteins, which also induce the polimerization of actin filaments and lastly the invagination of the cell membrane, thanks to the GTPase activity of dynamin. (B) Cell entry mechanisms exploited by human herpesviruses type 1 and type 2 (HSV-1 and HSV-2). The binding of viral glycoproteins B and D to their ligands triggers dimerization of the gH/gL complex, which causes the activation of the fusogenic activity of gB, enabling the release of the viral capsid into the cytosol. On the other hand, viral capsid delivery through the endosomal pathway has also been described, which is associated with endosomes having a low pH. (C) The mechanism used by varicella-zoster virus (VZV) for entering cells is also mediated by the gH/gL complex, but clathrin-mediated entry has also been described for this virus. (D) The Epstein–Barr virus (EBV) has been described to enter the cell through its binding to the EPHA2 receptor. Alternatively, other entry pathways exist, such as that mediated by BMRF-2 binding to integrins, causing gH/gL complex activation and gB-mediated fusion of membranes; lipid raft-mediated endocytosis; or viral entry through micro- and micropinocytosis. (E) The human cytomegalovirus (HCMV) mainly enters the cell via the activation of the gH/gL complex, triggering gB-mediated membrane fusion, but a low pH-dependent endocytosis mechanism has also been reported, involving a viral protein complex binding to host OR14I1. (F) The entry mechanisms exploited by human herpesviruses 6 (HHV-6; HHV-6A and HHV-6B) mainly occurs by endocytosis through lipid rafts. (G) The only entry mechanism described so far for the human herpesvirus 7 (HHV-7) is mediated by a fusogenic process mediated by the gH/gL complex. No endocytic pathway has been described yet for this virus. (H) Finally, Kaposi’s sarcoma-associated herpesvirus (KSV) infects the cells through a gB-mediated membrane fusion pathway, clathrin-mediated endocytosis and may also induce micro- and macropinocytosis.