Mechanisms of cell entry by human papillomaviruses: an overview

Abstract

As the primary etiological agents of cervical cancer, human papillomaviruses (HPVs) must deliver their genetic material into the nucleus of the target cell. The viral capsid has evolved to fulfil various roles that are critical to establish viral infection. The particle interacts with the cell surface via interaction of the major capsid protein, L1, with heparan sulfate proteoglycans. Moreover, accumulating evidence suggests the involvement of a secondary receptor and a possible role for the minor capsid protein, L2, in cell surface interactions.The entry of HPV in vitro is initiated by binding to a cell surface receptor in contrast to the in vivo situation where the basement membrane has recently been identified as the primary site of virus binding. Binding of HPV triggers conformational changes, which affect both capsid proteins L1 and L2, and such changes are a prerequisite for interaction with the elusive uptake receptor. Most HPV types that have been examined, appear to enter the cell via a clathrin-dependent endocytic mechanism, although many data are inconclusive and inconsistent. Furthermore, the productive entry of HPV is a process that occurs slowly and asynchronously and it is characterised by an unusually extended residence on the cell surface.Despite the significant advances and the emergence of a general picture of the infectious HPV entry pathway, many details remain to be clarified. The impressive technological progress in HPV virion analysis achieved over the past decade, in addition to the improvements in general methodologies for studying viral infections, provide reasons to be optimistic about further advancement of this field.This mini review is intended to provide a concise overview of the literature in HPV virion/host cell interactions and the consequences for endocytosis.

Figure 1

Putative model of interaction of HPV capsids with the ECM and cell surface. 1) HSPG, a widely expressed and evolutionary conserved cell surface receptor, is suggested as the initial attachment receptor for HPVs and is frequently found in the ECM and on the surface of most cells. HPV capsids have also been shown to bind to ECM-resident laminin-5 although this interaction seems to be of lesser importance for a productive infection. 2) Accumulating evidence suggests that a secondary receptor is involved in the infectious entry of HPV subsequent to HSPG interaction. The capsids are transferred to the putative secondary receptor on the cell surface. Whether transfer from primary ECM binding sites to primary cell surface binding sites occurs has not been directly investigated (dotted arrows). Capsid interaction with HSPG results in a conformational change that, in turn, results in the exposure of a furin cleavage site. Following this proteolytic cleavage, an additional conformational change exposes the binding site for the secondary cell surface receptor or lowers the affinity for the primary receptor which results in the hand-off to the second receptor, which then triggers endocytosis 3).