The structure of HSPGs is believed to be equally essential. For instance, O sulfation of HSPGs was sufficient for VLPs binding, which, however, was required together with N sulfation by pseudoviruses [
17]. This, nevertheless, has received little research. So far, it has been recognized that 2-O-sulfate groups, primarily located on iduronic acid residues in heparin and heparan sulfate, glucosmine N-sulfate and in particular glucosamine 6-O-sulfate groups of the polysaccharide all contribute to the interaction with HPV-16 VLPs. In addition, eight monosaccharide units of heparin were sufficient for the binding of HPV-16 VLPs, which increased as the heparin chain prolonged in size from eight to 14 units, but decreased with 16 or more units [
18].
It still remains mysterious whether α6 integrin or HSPGs is the genuine cellular receptor of HPV, for there are counterevidences and controversies for either. Several studies indicated that α6 integrin was dispensable for HPV-11 VLP binding to cells [
19], for BPV-4 infection [
29], as well as for HPV-16 and HPV-33 pseudoinfection [
20]. On the other hand, HSPGs, especially heparan sulfate, was not required for HPV31b virions infection of human keratinocytes
in vitro [
3]. However, Johnson et al recently showed the opposite results using the murine cervicovaginal challenge model that
in vivo HPV-31 infection was dependent on HSPGs [
30]. We put forwarded at least three possible explanations to the discrepancies between the outcomes. In the first place, it was largely that the different assay systems were employed since a standardized one was not available, where the viral particles could be VLPs, pseudovirions, or authentic virions; and the cell lines, diversified, including those derived from malignant carcinomas, such as Hela and HaCaT, etc, and the normal keratinocytes from human beings or animals. Different kinds of viral particles required different concentrations in assay. For example, MOIs in the setting of authentic virions ranged from 5 to 50 viral genome equivalents per cell, but reached thousands to tens of thousands per cell in most cases of VLP binding or pseudovirion pseudoinfection [
3]. And different cell lines presented distinct characteristics. Those transformed cells, which lost some of their epithelial characteristics, might result in disparities. Second, HPVs of different types employed distinct molecules as their own primary receptors. This could be the simplest explanation, which needs further evidence. In addition, further studies suggested that HPV infection was likely to engage more than one cellular surface protein, as in the case of a secondary receptor [
10,
19,
20,
23]. It was possible that HPVs utilized this strategy for infection that initial binding to a primary receptor and then transfer to a secondary receptor allowing for invasion of cells. Thus, it was most likely that both α6 integrin and HSPGs, functioning as primary or secondary receptor, contributed individually or in combination to the process. It should be noted that a virus receptor means a host surface component involved in binding and facilitating a viral infection. Therefore, we believe that both α6 integrin and HSPGs can be labeled HPV receptor, and that more receptors will be identified in the future.