Virus entry paradigms

Abstract

Viruses, despite being relatively simple in structure and composition, have evolved to exploit complex cellular processes for their replication in the host cell. After binding to their specific receptor on the cell surface, viruses (or viral genomes) have to enter cells to initiate a productive infection. Though the entry processes of many enveloped viruses is well understood, that of most non-enveloped viruses still remains unresolved. Recent studies have shown that compared to direct fusion at the plasma membrane, endocytosis is more often the preferred means of entry into the target cell. Receptor-mediated endocytic pathways such as the dynamin-dependent clathrin and caveolar pathways are well characterized as viral entry portals. However, many viruses are able to utilize multiple uptake pathways. Fluid phase uptake, though relatively non-specific in terms of its cargo, potentially aids viral infection by its ability to intersect with the endocytic pathway. In fact, many viruses despite using specialized pathways for entry are still able to generate productive infection via fluid phase uptake. Macropinocytosis, a major fluid uptake pathway found in epithelial cells and fibroblasts, is stimulated by growth factor receptors. Many viruses can induce these signaling cascades in cells leading to macropinocytosis. Though endocytic trafficking is utilized by both enveloped and non-enveloped viruses, key differences lie in the way membranes are traversed to deposit the viral genome at its site of replication. This review will discuss recent developments in the rapidly evolving field of viral entry.

Fig. 1

Multiple endocytic pathways operate at the plasma membrane and are utilized in viral entry. The clathrin coated pit pathway is the best characterized endocytic pathway and is used for entry by many viruses like the influenza virus, the herpes simplex virus (HSV), HIV-1, adenovirus and poliovirus. The induced caveolar pathway is the main entry portal for polyomaviruses like SV40 and echovirus. Many viruses are also internalized by clathrin and caveolin independent pathways, which are still not well understood in terms of cargo specificity and molecular players. Though the cartoon shows influenza virus, HSV, poliovirus and SV40 virus internalization via a clathrin and caveolin independent pathway, the independent pathway utilized by one virus may differ from that used by another virus. Macropinocytosis is triggered by virus binding and utilized by vaccinia virus and adenovirus

Fig. 2

Entry of a pH dependent enveloped virus. Many viruses are endocytosed via a clathrin-dependent pathway into clathrin coated pits. The clathrin coat is rapidly lost inside the cell and the vesicle matures into an early endosome. The acidic pH of the endosome brings about a conformational change in the viral envelope protein leading to fusion of the viral and endosomal membranes and capsid release into the cytosol. Genome release often occurs close to the viral replication centre. After capsid disassembly the viral RNA can initiate the replication cycle