How Human Papillomavirus Replication and Immune Evasion Strategies Take Advantage of the Host DNA Damage Repair Machinery

Abstract

The DNA damage response (DDR) is a complex signalling network activated when DNA is altered by intrinsic or extrinsic agents. DDR plays important roles in genome stability and cell cycle regulation, as well as in tumour transformation. Viruses have evolved successful life cycle strategies in order to ensure a chronic persistence in the host, virtually avoiding systemic sequelae and death. This process promotes the periodic shedding of large amounts of infectious particles to maintain a virus reservoir in individual hosts, while allowing virus spreading within the community. To achieve such a successful lifestyle, the human papilloma virus (HPV) needs to escape the host defence systems. The key to understanding how this is achieved is in the virus replication process that provides by itself an evasion mechanism by inhibiting and delaying the host immune response against the viral infection. Numerous studies have demonstrated that HPV exploits both the ataxia-telangiectasia mutated (ATM) and ataxia-telangiectasia and rad3-related (ATR) DDR pathways to replicate its genome and maintain a persistent infection by downregulating the innate and cell-mediated immunity. This review outlines how HPV interacts with the ATM- and ATR-dependent DDR machinery during the viral life cycle to create an environment favourable to viral replication, and how the interaction with the signal transducers and activators of transcription (STAT) protein family and the deregulation of the Janus kinase (JAK)-STAT pathways may impact the expression of interferon-inducible genes and the innate immune responses.

Keywords: ATM; ATR; DNA damage repair (DDR); IFN-γ; STAT-5; human papillomavirus (HPV); viral immune evasion.

Figure 1

Epithelial differentiation triggers the productive phase of the HPV life cycle. The figure shows a diagram of a stratified epithelium. HPV-infected cells are shown with pink nuclei. HPV infects the basal keratinocytes of the stratified epithelium through a microwound (as shown by the black arrow on the left). Epithelial differentiation triggers the amplification phase of HPV life cycle, followed by late gene expression and virion assembly. The increased HPV replication is shown in the diagram by more numerous and larger pink circles, which indicate an increase of both viral replication centers and DNA damage foci.

Figure 2

Schematic representation of the HPV strategies likely to modify the immunological microenvironment in the site of infection. HPV has evolved mechanisms both to avoid initial recognition by the immune system as well as to interfere with adaptive immunity. A primary mechanism of viral immune evasion is likely achieved by avoiding antigen processing and presentation by Langerhans and dendritic cells (represented in the diagram as a lack of migration of these cells from the dermis). Further, HPV has evolved mechanisms capable of inhibiting key host antivirus natural and adaptive responses, including the modulation of the cascade of inflammatory or immunoregulatory cytokines and chemokines, IFN production, as well as the activity of cytotoxic T cells and natural killer cells, and the humoral antibody response. The recruitment of CD4⁺ CD25⁺ regulatory T cells (Tregs, depicted as green circles) and the presence of activated Th2 cells (depicted as red circles), can lead to a further suppression of cytotoxic functions, induction of T cell anergy, and apoptosis. The pink nuclei identify the HPV-infected epithelium. The up and down arrows represent the increased or decreased expression of cell markers or cytokines.