Persistence of viral DNA in the epithelial basal layer suggests a model for papillomavirus latency following immune regression

Abstract

Rabbit oral papillomavirus (ROPV) causes benign and spontaneously regressing oral lesions in rabbits, and is a useful model of disease associated with low-risk human papillomavirus types. Here we have adapted the ROPV system to study papillomavirus latency. Following lesion regression, ROPV DNA persists at the majority of regressed sites at levels substantially lower than those found in productive papillomas. Spliced viral transcripts were also detected. ROPV persistence in the absence of disease could be demonstrated for a year following infection and lesion-regression. This was not associated with completion of the virus life-cycle or new virion production, indicating that ROPV persists in a latent state. Using novel laser capture microdissection techniques, we could show that the site of latency is a subset of basal epithelial cells at sites of previous experimental infection. We hypothesize that these cells are epithelial stem cells and that reactivation of latency may be a source of recurrent disease.

The known unknowns of HPV natural history

“…These transcripts, which can act as oncogenes, were induced with UV light activation; 40% of latent sites had detectable E6/E7 mRNA, and 27% formed papillomas. Recent studies in the cottontail oral papillomavirus (COPV) model provide similar evidence for latency, though early viral gene transcription in the latent COPV sites included E6/E7 mRNA, while late viral protein expression was not detectable (63). The same study used laser capture microdissection to localize the site of latency to the epidermal stem cell.…”

“…However, animal models of papillomavirus infection have provided sufficient experimental evidence for papillomavirus latency (63). A prototypical example is cottontail rabbit papillomavirus (CRPV), which infects the hairy skin epithelium of its host.…”

“…A few infected basal stem cells will retain HPV episomes, but do not differentiate, and these infected cells are unlikely to be sampled using standard exfoliative techniques employed in most epidemiologic studies, which sample only the surface epithelium. Thus, HPV in a basal stem cell may remain undetectable until triggered to differentiate by undetermined stimuli such as wound repair and hormonal regulation (63,69). With high cellular turnover in the cervical epithelium, one may expect relatively constant detection of HPV in this model.…”

Pathology: Three questions

“…By dissecting the tissue with a laser, the researchers were able to investigate the process in unprecedented detail 3 . The group's findings "prove that papillomaviruses can persist in the site of infection after lesion clearance and that their genomes are found in the basal layer [of the mucosa] with little evidence of productive infection in the layers above", says Doorbar.…”

Reconsidering Primary HPV Testing in Cervical Cancer Screening

“…Finally, HPV may remain in a latent state for years before causing disease [23], so that it is usually not possible to determine when and from whom initial infection was acquired. Most incident HPV infections are attributable to past, not current, sexual behavior, supporting a natural history model of viral latency and reactivation [24].…”