The biology of papillomavirus latency

Abstract

The presence of viral DNA in the absence of disease has suggested that papillomaviruses, like many other viruses, can exist as latent infections in the skin or other epithelial sites. In animal models, where detailed investigation has been carried out, papillomavirus DNA can be found at sites of previous infection following immune regression, with the site of latent infection being the epithelial basal layer. Such studies suggest that immune surveillance can restrict viral gene expression in the basal and parabasal layers without efficiently suppressing viral genome replication, most probably through the action of memory T-cells in the skin or dermis. Although gradual papillomavirus genome loss appears to occur over time at latent sites, immunosuppression can arrest this, and can lead to an elevation in viral genome copy number in experimental systems. In addition to immune-mediated latency, it appears that a similar situation can be achieved following infection at low virus titres and/or infection at epithelial sites where the virus life cycle is not properly supported. Such silent of asymptomatic infections do not necessarily involve the host immune system and may be controlled by different mechanisms. It appears that virus reactivation can be triggered by mechanical irritation, wounding or by UV irradiation which changes the local environment. Although the duration of papillomavirus latency in humans is not yet known, it is likely that some of the basic principles will resemble those elucidated in these model systems, and that persistence in the absence of disease may be the default outcome for at least some period of time following regression.

Keywords: HPV; Papillomavirus; basal cell; immune regression; immunosuppression.; latency; stem cell.

Fig. (1)

Different Outcomes of Papillomavirus Infection. (A) Papillomavirus DNA can be detected in epithelial tissues because of its presence as virus particles on the epithelial surface. The detection of papillomavirus DNA in such situations can be misinterpreted as papillomavirus latency. To cause a lesion and/or to initiate a latent infection, the virus particles have to gain access to the epithelial basal cells at sufficiently high levels. Each papillomavirus type has specific epithelial sites where it can initiate a productive life cycle, as well as sites where virus entry occurs in the absence of lesion formation. Such epithelial tropisms are not yet understood at the molecular level. (B) Depending on the epithelial site, the virus titre, and the tropism of the particular papillomavirus, it appears that several outcomes can result. At low titres and/or at non-permissive epithelial sites, an asymptomatic or silent infection may ensue, in which viral genomes may persist in the basal layer without appropriate gene expression or lesion formation. While this is a form of latency, such silent infections do not necessarily involve the immune system, and are distinguished here from latency mediated by the immune-system Alternatively a productive infection may develop, in which viral gene expression is properly regulated as the infected cell migrates through the epithelium. With some HPV types (e.g. high-risk types) and at particular epithelial sites, deregulated viral gene expression can lead to neoplasia. Cervical Intraepithelial Neoplasia (CIN) of different grades can occur following high-risk HPV infection of the cervix. (C) Persistent high-risk HPV infection can predispose to the accumulation of genetic errors and the progression to cancer at certain epithelial sites (e.g. the cervical transformation zone). Most infections are transient however and are resolved by the host immune system. Although immune surveillance may suppress viral gene expression in the epithelium, failure of the immune system to clear viral genomes from the epithelial basal layer would explain papillomavirus latency.

Fig. (2)

Model of Papillomavirus Latency based on Animal Studies. (1) Active Infection. Active papillomavirus infection involves the regulated expression of viral proteins as cells containing viral genomes migrate towards the epithelial surface. The onset of viral genome amplification (light blue) and L1 expression (yellow) facilitates the assembly and eventual release of virions from the epithelial surface. Cells that are ‘in the cell cycle’ and which may proceed through cell division are marked with red nuclei. In the upper epithelial layers, cell cycle entry is driven by the viral E6 and E7 proteins. The virus-infected cells of the epithelial basal layer maintain the viral genome as a low copynumber episome with only low-levels of viral gene expression. Long-term persistence may require the maintenance of the viral genome in an epithelial ‘stem cell’ (highlighted in the basal layer). Resting T-cells (brown) and Langerhans cells (orange) can be found in the lower layers of the epithelium and in the dermis. The positions of these resting T-cells (brown circular cells) are indicated in the diagram. (2) Immune Regression. Immune regression involves the presentation of viral antigens to the immune system, (probably via the Langerhans cells) and the subsequent accumulation of activated CD4+ and CD8+ T-cells (light blue circular cells) in and around the lesion. During regression, activated T-cells accumulate within and beneath the lesion. (3) Latency. Lesion clearance involves the suppression of viral gene expression as lymphocytes infiltrate, and may involve changes in cytokine activity and cytokine signaling at the site of regression. The ongoing proliferation of virus-containing basal cells in the absence of normal viral gene expression appears to underlie lesion clearance. Changes in viral gene expression in the replicating basal cells may explain the slow decline in viral genome copy number over time at the site of previous infection. Current thinking suggests that the papillomavirus genome may persist long-term in the slow-cycling stem cells or stemlike cells. (4) Reactivation from Latency. This model may explain the changes in viral copy number that are thought to accompany immunosuppression. The presence of memory T-cells circulating in the epithelium prevent extensive viral gene expression and keep the viral genomes in the basal layer in a latent state. Changes in immune status would allow local rises in viral copy-number, and the possible reappearance of visible papillomas.