Abstract
Although many high-risk mucosal and cutaneous human papillomaviruses (HPVs) theoretically have the potential to synthesize L1 isoforms differing in length, previous seroepidemiological studies only focused on the short L1 variants, co-assembling with L2 to infectious virions. Using the multimammate mouse Mastomys coucha as preclinical model, this is the first study demonstrating seroconversion against different L1 isoforms during the natural course of papillomavirus infection. Intriguingly, positivity with the cutaneous MnPV was accompanied by a strong seroresponse against a longer L1 isoform, but to our surprise, the raised antibodies were non-neutralizing. Only after a delay of around 4 months, protecting antibodies against the short L1 appeared, enabling the virus to successfully establish an infection. This argues for a novel humoral immune escape mechanism that may also have important implications on the interpretation of epidemiological data in terms of seropositivity and protection of PV infections in general.
Highlights
Human Papillomaviruses (HPVs) are widely distributed in nature and more than 220 types were sequenced up to date (PaVE: Papillomavirus Episteme)
Depending on environmental factors (Rollison et al, 2019; Uberoi et al, 2016), the individual immune status (Reusser et al, 2015; Vinzon and Rosl, 2015) or genetic predispositions (e.g. EVER1/2 mutations in Epidermodysplasia verruciformis patients), commensal cutaneous papillomaviruses can induce hyperproliferative lesions which may progress to squamous cell carcinomas (SCCs) (Hasche et al, 2018)
Based on two previous studies comparing the presence of initiation codons within the papillomavirus L1 open reading frame (ORF) (Joh et al, 2014; Webb et al, 2005), their position was aligned according to the PV genera derivation (Bzhalava et al, 2015; Van Doorslaer et al, 2013; Figure 1)
Summary
Human Papillomaviruses (HPVs) are widely distributed in nature and more than 220 types were sequenced up to date (PaVE: Papillomavirus Episteme). Fu et al have used the Southern multimammate mouse, Mastomys coucha, as a model system for an HPV infection to uncover how papillomaviruses can avoid the immune response This African rodent is naturally infected with a skin papillomavirus called MnPV which, like its counterpart in humans, can trigger the formation of skin warts and malignant skin tumors. Fu et al went on to show that the antibodies that recognized the longer variants of L1 protein where “non-neutralizing”, meaning that could not block the spread of the virus, which is a prerequisite for immunity It was only after a delay of four months that the animals started making neutralizing antibodies that were directed against the shorter L1 proteins that makes up the virus’s protective coat. We characterized this mechanism in greater detail since it may have important implications in understanding the humoral immune response during a normal infection cycle in general
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