Pathways for HPV Entry into Cells

HPV Entry Into Cells

HPV entry into host cells is a complex process that involves the interaction between viral capsid proteins and cellular receptors. To initiate infection, HPV must first attach to the cell surface. The major capsid protein, L1, plays a significant role in initial attachment, as it interacts with various cell types due to its low specificity. However, a more specific interaction between the L2 protein and cellular receptors is required for subsequent steps in viral entry. It is proposed that a specific region in the L2 protein interacts with a cell surface molecule after the virus attaches to a primary receptor. This interpretation implies that a conformational change occurs at the cell surface after attachment, revealing this specific domain in L2. This process is similar to other viruses that trigger downstream events through conformational changes to facilitate interactions with secondary receptors.

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Previous studies have suggested several potential cellular receptors such as α6 integrin and heparan sulfate proteoglycans (HSPGs) are involved in the binding and entry of HPV. The HPV virus interacts with these elusive receptor complexes and is subsequently internalized through non-traditional endocytosis mechanisms. It is worth noting that different types of HPV enter cells through different pathways, including caveolar endocytosis, clathrin-mediated endocytosis, and clathrin- and caveolar-independent endocytosis.

Subsequently, during intracellular transport, it has been demonstrated that the virus first localizes in the endosome system, trans-Golgi-network (TGN), Golgi complex, and endoplasmic reticulum (ER), and then is transported to the nucleus where viral DNA replicates.

Figure 1. Endocytic pathways of HPVs.
(Source: Letian, T. et al., 2010)

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Caveolar Endocytosis

Caveolar endocytosis, as an alternative uptake pathway, is less common than clathrin-mediated endocytosis for the entry of viruses into cells. This pathway is primarily utilized by nonenveloped viruses with a size of less than 55 nm, including HPVs. Compared to clathrin-mediated entry, this pathway occurs at a slower rate. The resulting vesicles formed during caveolar endocytosis do not undergo acidification. The process of caveolar endocytosis involves the formation of caveolar vesicles that pinch off from the plasma membrane, enclosing the virus and allowing it to enter the cell. This pathway provides an alternative route for HPV entry, particularly in cells that lack or have reduced levels of clathrin-coated pits.

Furthermore, caveolar endocytosis may contribute to the intracellular trafficking of HPV after internalization. Caveolae, with their unique properties and association with specific signaling molecules, may participate in directing HPV-containing vesicles to specific intracellular compartments. Studies have shown that caveolar endocytosis passes through the caveosomes, bypasses endosomes, and ultimately reaches the Golgi body and/or endoplasmic reticulum (ER). HPV-31 has been found to utilize caveolar endocytosis to enter cells, as supported by multiple investigations.

Notably, caveolar entry and clathrin-dependent endocytosis are not separate pathways, and there is a crosstalk between these pathways that allows cargo to move between them with some molecules involved, such as Rab 5 GTPase.