The carcinogenicity of human papillomavirus types reflects viral evolution

Abstract

Persistent infections with carcinogenic human papillomaviruses (HPV) cause virtually all cervical cancers. Cervical HPV types (n > 40) also represent the most common sexually transmitted agents, and most infections clear in 1-2 years. The risks of persistence and neoplastic progression to cancer and its histologic precursor, cervical intraepithelial neoplasia grade 3 (CIN3), differ markedly by HPV type. To study type-specific HPV natural history, we conducted a 10,000-woman, population-based prospective study of HPV infections and CIN3/cancer in Guanacaste, Costa Rica. By studying large numbers of women, we wished to separate viral persistence from neoplastic progression. We observed a strong concordance of newly-revised HPV evolutionary groupings with the separate risks of persistence and progression to CIN3/cancer. HPV16 was uniquely likely both to persist and to cause neoplastic progression when it persisted, making it a remarkably powerful human carcinogen that merits separate clinical consideration. Specifically, 19.9% of HPV16-infected women were diagnosed with CIN3/cancer at enrollment or during the five-year follow-up. Other carcinogenic types, many related to HPV16, were not particularly persistent but could cause neoplastic progression, at lower rates than HPV16, if they did persist. Some low-risk types were persistent but, nevertheless, virtually never caused CIN3. Therefore, carcinogenicity is not strictly a function of persistence. Separately, we noted that the carcinogenic HPV types code for an E5 protein, whereas most low-risk types either lack a definable homologous E5 ORF and/or a translation start codon for E5. These results present several clear clues and research directions in our ongoing efforts to understand HPV carcinogenesis.

HPV-16 E5 oncoprotein upregulates lipid raft components caveolin-1 and ganglioside GM1 at the plasma membrane of cervical cells

“…A study of HPV infection and cervical cancer finds that carcinogenic HPV types encode an E5 protein, whereas most low-risk HPV types lack an E5 gene or a translation start codon for E5 (Schiffman et al, 2005). Additionally, targeted expression of 16E5 in basal epithelial cells of transgenic mice induces skin tumors at a high frequency (Genther-Williams et al, 2005), and estrogen-treated transgenic mice that express HPV-16 E5, E6 and E7 develop a higher number of cervical cancers than transgenic mice that express E6 and E7 without E5 (Riley et al, 2003).…”

Identificação de tipos de papilomavirus e de outros fatores de risco para neoplasia intra-epitelial cervical

“…O percentual de positividade nos casos é semelhante ao encontrado na literatura 62, 78,5, 82, e 91,2% 9,[18][19][20][21] . A diferente distribuição de tipos oncogênicos nas populações, tal como constata-se na literatura, tem importância na produção de vacinas adequadas a cada região, contendo os tipos virais mais prevalentes 12 .…”

“…A não identificação de HPV em todos os casos de NIC pode resultar de alguns fatores, entre os quais: problemas na coleta dos espécimes; dificuldade nos testes para HPV existentes, em decorrência da incompleta quantidade de vírus descobertos, e limitações dos testes atuais 21 .…”

“…Mesmo confeccionadas com finas cerdas, as escovas utilizadas para coleta do material endocervical para colpocitologia produziam, com freqüência, discreto sangramento, principalmente quando havia inflamação cervicovaginal. O espécime sanguinolento contém hemoglobina suficiente para impedir o processo de amplificação molecular 21 . Mesmo no afã de identificar o vírus, não se poderia prejudicar a avaliação citomorfológica das pacientes, colhendo espécime para PCR em primeiro lugar e postergando a obtenção do espécime para estudo citológico, que resultaria no retardo do diagnóstico e do tratamento, com suas negativas conseqüências.…”

Die Infektion mit humanen Papillomaviren

“…In einer groß angelegten dänischen Studie zeigten Kjaer et al nach 2-maligem HPV-16-Nachweis eine CIN-2/3-Inzidenz von 50% innerhalb von 10 Jahren [13]. Insgesamt zeigen die verschiedenen HR-HPV-Typen ein unterschiedliches Maß an transformierendem Potenzial [11,22]. Daneben spielen andere Faktoren, wie Nikotinabusus, Vielgeburtlichkeit und die Benutzung oraler Kontrazeptiva eine nur untergeordnete Bedeutung [23].…”