Scripties UMCG - Rijksuniversiteit Groningen
 
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The Inhibitory Role of Human a-defensin 5 in HPV16 Uptake and Infection

(2017) Voss, F. (Féline)

Human papillomavirus (HPV) is the number one sexually transmitted virus worldwide, of
which high-risk HPV type 16 (HPV16) is causally associated with 50% of all cervical cancers
and 90% of HPV-positive oropharyngeal cancers. Defensins are small peptides of the innate
immune system that are expressed by epithelial cells in the genitourinary tract. Human adefensin
5 (HD5) has been shown to inhibit HPV16 infection. However, the mechanisms
proposed by different studies are conflicting. Therefore, we have aimed to delineate the role
of defensins in HPV16 uptake, infection, and its mucosal immune responses. Our study shows
that HPV16 infection is blocked to near 100% when pretreating HPV16 PsV with HD5,
indicating that HD5 does not require direct surface interaction with cellular receptors to block
infection. Uptake assays give evidence that HD5 pretreated HPV16 are internalized by the
cell, but are unable to reach the nucleus. In fact, a build-up of virus particles within acidic
environments of the cell was observed, suggesting viral trafficking was halted at late
endosomes or possibly lysosomes. From this data we conclude that HD5 interacts directly
with the viral capsid, resulting in a build-up of virus particles in late endosomes and
prevention of viral trafficking to the nucleus that completes infection. Throughout the
investigation we have continuously refined our hypothesis for the mechanism by which HD5
blocks HPV16 infection. As viral uncoating is required for the HPV16 to escape the late
endosomes, we currently hypothesize that HD5 inhibits this viral capsid dissociation by
stabilizing the viral capsid.






 
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