Organization of Human Papillomavirus Productive Cycle during Neoplastic Progression Provides a Basis for Selection of Diagnostic Markers

Abstract

The productive cycle of human papillomaviruses (HPVs) can be divided into discrete phases. Cell proliferation and episomal maintenance in the lower epithelial layers are followed by genome amplification and the expression of capsid proteins. These events, which occur in all productive infections, can be distinguished by using antibodies to viral gene products or to surrogate markers of their expression. Here we have compared precancerous lesions caused by HPV type 16 (HPV16) with lesions caused by HPV types that are not generally associated with human cancer. These include HPV2 and HPV11, which are related to HPV16 (supergroup A), as well as HPV1 and HPV65, which are evolutionarily divergent (supergroups E and B). HPV16-induced low-grade squamous intraepithelial lesions (CIN1) are productive infections which resemble those caused by other HPV types. During progression to cancer, however, the activation of late events is delayed, and the thickness of the proliferative compartment is progressively increased. In many HPV16-induced high-grade squamous intraepithelial lesions (CIN3), late events are restricted to small areas close to the epithelial surface. Such heterogeneity in the organization of the productive cycle was seen only in lesions caused by HPV16 and was not apparent when lesions caused by other HPV types were compared. By contrast, the order in which events in the productive cycle were initiated was invariant and did not depend on the infecting HPV type or the severity of disease. The distribution of viral gene products in the infected cervix depends on the extent to which the virus can complete its productive cycle, which in turn reflects the severity of cervical neoplasia. It appears from our work that the presence of such proteins in cells at the epithelial surface allows the severity of the underlying disease to be predicted and that markers of viral gene expression may improve cervical screening.

Integration of the HPV16 genome does not invariably result in high levels of viral oncogene transcripts

“…The most probable explanation for this is the sampling strategy used (biopsies versus cervical scrapes). Although analyses of exfoliated cells enable an easy access to clinical material and are clearly ideal in a diagnostic setting the results are not representative for the overall quantity of the RNA or for the diversity of viral mRNA species in the underlying lesions (Middleton et al, 2003). Moreover, in our study we did not relate E6/E7 expression levels to viral genome copy number.…”

Prevalence of Human Papillomavirus in Women from Saudi Arabia

“…The World Health Organization has officially designated HPVs -16 and -18 as carcinogenic agents. According to earlier information, and -82 were classified as "high-risk types" (Munoz et al, 2003;Bouvard et al, 2009), and associated with cervical cancer; while were classified as "low-risk types" (Middleton et al, 2003;Trottier and Burchell, 2009), which were found difficult for detection in cervical lesions but associated with anogenital warts.…”

HPV in situ hybridization: Impact of different protocols on the detection of integrated HPV

“…One factor considered to be of key importance for the progression of intraepithelial lesions to invasive disease is integration of HPV into the host cell genome. 2,[7][8][9] The majority of CIN II/III lesions and all ICCs are infected with high risk (oncogenic) HPV types, particularly HPV 16 and 18. The E2 region of the HPV genome, which is involved in the regulation of the oncogenic HPV E6 and E7 proteins, is frequently disrupted when the virus is integrated.…”