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Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/113948
Connection between viral genetic diversity and clinical manifestation of Papillomavirus infection = Connexió entre la diversitat de genotips virals i les manifestacions clíniques de la infecció pel virus del Papil·loma
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[eng] Papillomaviruses (PVs) are a numerous family of small dsDNA viruses infecting virtually all mammals. PVs cause infections without triggering a strong immune response, and natural infection provides only limited protection against reinfection. Most PVs are part and parcel of the skin microbiota. In some cases, infections by certain PVs take diverse clinical presentations, from highly productive self-limited warts to invasive cancers. The main aim of this thesis is explore the link between HPV genotypic diversity and the phenotypic, clinical diversity of the diseases associated with HPV infection by means of evolutionary, clinical and ecologically approaches.
From and evolutionary perspective, we studied the codon usage preferences of HPVs. By applying phylogenetic inference and dimensionality reduction methods, we found that phylogenetic relationships between HPVs explained only a small proportion of codon usage preferences (CUPrefs) variation. Instead, the most important explanatory factor for viral CUPrefs was infection phenotype, as orthologous genes in viruses with similar clinical presentation displayed similar CUPrefs. Moreover, viral genes with similar spatiotemporal expression patterns also showed similar CUPrefs. Moreover, we also found that HPV genes with similar spatiotemporal expression patterns displayed similar CUPrefs. Hence, Our results suggest that CUPrefs in HPVs reflect either variations in the mutation bias or differential selection pressures depending on the clinical presentation and expression timing.
From a clinical point of view, first, we studied the distribution patterns of oncogenic and non-oncogenic HPVs in anal and perianal Squamous Intraepithelial Lesions (SIL) in non-vaccinated heterosexual men, women, and Men who have sex with men (MSM) with known HIV status. We found that there is an increased prevalence of low-grade perianal lesions driven only by oncogenic HPVs. We also found a high prevalence of anal SIL containing foci of high-grade SIL exclusively driven by non-oncogenic HPVs. Our results suggest that there is a disagreement in high-grade/low-grade intraepithelial neoplasia and oncogenic/non-oncogenic HPV infection. Second, we analyzed the presence of HPVs not explicitly targeted by standard molecular epidemiologic methods of detection in squamous carcinoma samples of the vulva, penis and head and neck. These three anatomical locations display a low fraction of cancer cases attributable to HPVs, in sharp contrast with the higher rates of viral DNA prevalence in anal and cervical carcinomas. The standard HPV detection methods target only a subset of clinically important HPVs, namely oncogenic AlphaPVs, and may thus overlook the presence of other HPVs. We tested 2365 samples and found 6 samples containing cutaneous HPVs, suggesting that certain cutaneous HPVs, typically classified as “non- oncogenic” HPVs, may be linked to small number of cancer cases and call for further studies to elucidate the pathogenic role and malignisation mechanism of these HPVs.
Finally, from an ecological perspective, we studied the interaction among HPVs inside its host in different stages of the cervical infection and different anatomical regions. By applying established ecological methods, we found that HPVs interact within the host, and that the presence of one given HPV is not neutral for the rest of the HPVs infecting the host. We also study how the interaction among HPVs could be affected by the introduction of ecological pressures linked to vaccination. By applying the same ecological methods, we find that in the initial descriptions of the post-vaccination era, HPVs still form non-neutral communities suggesting that the vaccine is not changing the underlying processes that govern HPV distributions and relative abundances.
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FÉLEZ SÁNCHEZ-OCAÑA, Marta. Connection between viral genetic diversity and clinical manifestation of Papillomavirus infection = Connexió entre la diversitat de genotips virals i les manifestacions clíniques de la infecció pel virus del Papil·loma. [consulta: 10 de desembre de 2025]. [Disponible a: https://hdl.handle.net/2445/113948]