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  • Endocytosis or veropexis is the most common cellular entry technique for viruses
  • Once the cell internalizes the virus, it is then delivered to an acidic pit, a so-called early endosome. The virus then may be transferred into a late endosome and then to a lysosome.
  • Alternatively, due to the low pH value in the lumen of endosomes, the viral membrane can fuse with the endosomal membrane, releasing the viral genome into the cytoplasm.
  • After exiting from endosomes, some adenoviruses or poxviruses may use microtubules for transport within the cytoplasm.
  • Once in the cytoplasm, some viruses move toward the nucleus to deliver their cargo inside the nucleus, whereas the nucleocytoplasmic large DNA viruses (NCLDVs) belonging to the families Ascoviridae, Asfarviridae, Iridoviridae, Phycodnaviridae, and Poxviridae, and giant viruses belonging to the families Mimiviridae and Marseilleviridae usually remain in the cytoplasm to initiate their replication cycle.
  • Dynamin GTPase may have a key role in regulating most endocytic pathways.
  • During virus entry, dynamin is deposited in the neck of the endocytic pit toward the cytoplasm leading to the excision of the pit.
  • There are several major endocytosis-based pathways that viruses can use to enter cells and evade the host’s immune system.
  • These pathways differ in terms of the types of particles involved and the molecules that are important in the process. The most important viral entry pathways are as follows:

a) Pinocytosis (cell drinking), which is the process by which cells take up solutes and fluids. Pinocytotic processes can be further classified based on the membrane structures and types of molecules they are associated with. Macropinocytosis is a nonspecific process, and particles internalized by this route may not be essential for the cell. When it is exploited by viruses, interactions between viral proteins and cell receptors activate intracellular signaling and actin rearrangements that form ruffles or filopodia on the external surface of the host cell. The ruffles then close up to form a vesicle known as a macropinosome, which carries the virus into the cytosol. Actin, Rho GTPases (Rac and Cdc42), PI3K, and Na+/H+ exchange are usually required for this pathway, and kinases are required to regulate macropinosome formation and closure.

b) Clathrin-dependent endocytosis, which is the process by which the cell internalizes the virus in a clathrin-rich flask-shaped invagination/cavity (vesicle) known as a clathrin-coated pit. The virus is then delivered into the cytoplasm via endosomes. Clathrin and cholesterol are required, and dynamin and transferrin are usually involved in pit formation.
c) Caveolar-dependent endocytosis, which is similar to clathrin-mediated endocytosis but involves pits containing caveolin-1 rather than clathrin. The internalized virus is delivered to the cytoplasm in cave-like bodies known as caveolae or caveosomes, whose internal pH is neutral.
d) Clathrin- and caveolin-1–independent endocytosis: refer to mechanisms by which viruses can enter host cells without relying on clathrin-coated pits or caveolae-mediated endocytosis (involve vesicles that contain neither clathrin nor caveolin), which are common pathways for cellular uptake. However, like the clathrin- and caveolin-based pathways, they generally require dynamin, cholesterol, and/or lipids.
e) Dynamin-independent endocytosis: Dynamin is a GTPase protein involved in the scission of clathrin-coated vesicles during clathrin-mediated endocytosis. Some viruses, such as simian virus 40 (SV40), can enter host cells via dynamin-independent endocytosis, bypassing the need for dynamin-mediated membrane scission.
f) Cholesterol-dependent entry: While caveolin-mediated endocytosis is dependent on cholesterol-rich membrane microdomains known as lipid rafts, some viruses, such as human papillomavirus (HPV), can enter host cells via a cholesterol-dependent mechanism independent of caveolin.
g) Filopodia-mediated entry: Certain viruses, including Ebola virus and Marburg virus, can exploit filopodia, thin membrane protrusions supported by actin filaments, for entry into host cells. These viruses can bind to filopodia and induce their retraction, bringing the virus particles closer to the cell membrane for entry.
Further Reading
  1. Virus entry: molecular mechanisms and biomedical applications
  2. Virus entry paradigms
  3. Virus-Receptor Interactions and Receptor-Mediated Virus Entry into Host Cells
  4. The cell biology of receptor-mediated virus entry