(1) Most virions bind to primary attachment receptors, HSPG1, present in ECM (basement membrane in vivo) or on the cell surface. HPV11 capsids have also been shown to bind to ECM-resident laminin 5 (LN5). Viral particles are transported towards the cell body along actin-rich protrusions. (2) Capsids engage with secondary HSPG binding sites present on the cell surface (HSPG2). Whether transfer from primary ECM binding sites to primary cell surface binding sites occur has not been directly investigated. Interaction with the HSPG2 cell surface receptor induces conformational changes in L1 and L2 resulting in the exposure of the L2 amino terminus and subsequent furin cleavage at a conserved cleavage site. Host cell CyPB facilitates the L2 conformation changes. (3) These events may induce an additional conformational change that either reduces the affinity of capsids to HSPG or result in exposure of sites required for handover to a putative non-HSPG uptake receptor, which then triggers endocytosis.

(A) Structure of a T=7 HPV16 capsid according to [12, 13]. (B) L1 monomer; α-helices are highlighted in pink; all five surface loops are marked in addition to the internal C-D loop. (C) top view of a L1 pentamer (spacefill); individual L1 molecules are displayed in different colors to highlight the intertwining of the molecules. (D) L1 invading C-terminal arm model as proposed by [13]. Side view of a pentamer in addition to a single L1 molecule from the neighboring capsomere is shown in spacefill. The arrow points to the intercapsomeric disulfide bond. Images were downloaded from the RCSB Protein Data Bank (www.rcsb.org) and modified using RasMol (A, C) and JMol (B, D) software.

Schematic diagrams of the entry pathways proposed for various PV types. HPV16 is endocytosed via a clathrin- and caveolin-independent pathway, whereas BPV1 and HPV31 were shown to enter via clathrin-coated pits and caveolae, respectively. For more details see main text.