Epithelial Cell Responses to Infection with Human Papillomavirus
Top Cited Papers
- 1 April 2012
- journal article
- review article
- Published by American Society for Microbiology in Clinical Microbiology Reviews
- Vol. 25 (2), 215-222
- https://doi.org/10.1128/cmr.05028-11
Abstract
SUMMARY: Human papillomavirus (HPV) infection of the genital tract is common in young sexually active individuals, the majority of whom clear the infection without overt clinical disease. Most of those who do develop benign lesions eventually mount an effective cell-mediated immune (CMI) response, and the lesions regress. Regression of anogenital warts is accompanied histologically by a CD4 + T cell-dominated Th1 response; animal models support this and provide evidence that the response is modulated by antigen-specific CD4 + T cell-dependent mechanisms. Failure to develop an effective CMI response to clear or control infection results in persistent infection and, in the case of the oncogenic HPVs, an increased probability of progression to high-grade intraepithelial neoplasia and invasive carcinoma. Effective evasion of innate immune recognition seems to be the hallmark of HPV infections. The viral infectious cycle is exclusively intraepithelial: there is no viremia and no virus-induced cytolysis or cell death, and viral replication and release are not associated with inflammation. HPV globally downregulates the innate immune signaling pathways in the infected keratinocyte. Proinflammatory cytokines, particularly the type I interferons, are not released, and the signals for Langerhans cell (LC) activation and migration, together with recruitment of stromal dendritic cells and macrophages, are either not present or inadequate. This immune ignorance results in chronic infections that persist over weeks and months. Progression to high-grade intraepithelial neoplasia with concomitant upregulation of the E6 and E7 oncoproteins is associated with further deregulation of immunologically relevant molecules, particularly chemotactic chemokines and their receptors, on keratinocytes and endothelial cells of the underlying microvasculature, limiting or preventing the ingress of cytotoxic effectors into the lesions. Recent evidence suggests that HPV infection of basal keratinocytes requires epithelial wounding followed by the reepithelization of wound healing. The wound exudate that results provides a mechanistic explanation for the protection offered by serum neutralizing antibody generated by HPV L1 virus-like particle (VLP) vaccines.Keywords
This publication has 81 references indexed in Scilit:
- Efficacy of Quadrivalent HPV Vaccine against HPV Infection and Disease in MalesThe New England Journal of Medicine, 2011
- Epidemiological Study of Anti-HPV16/18 Seropositivity and Subsequent Risk of HPV16 and -18 InfectionsJNCI Journal of the National Cancer Institute, 2010
- In Vivo Mechanisms of Vaccine-Induced Protection against HPV InfectionCell Host & Microbe, 2010
- Classification of papillomaviruses (PVs) based on 189 PV types and proposal of taxonomic amendmentsVirology, 2010
- The initial steps leading to papillomavirus infection occur on the basement membrane prior to cell surface bindingProceedings of the National Academy of Sciences of the United States of America, 2009
- Viral entry mechanisms: human papillomavirus and a long journey from extracellular matrix to the nucleusThe FEBS Journal, 2009
- Skin immune sentinels in health and diseaseNature Reviews Immunology, 2009
- Efficacy of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by oncogenic HPV types (PATRICIA): final analysis of a double-blind, randomised study in young womenThe Lancet, 2009
- Mechanisms of Human Papillomavirus Type 16 Neutralization by L2 Cross-Neutralizing and L1 Type-Specific AntibodiesJournal of Virology, 2008
- Neutralization of Human Papillomavirus with Monoclonal Antibodies Reveals Different Mechanisms of InhibitionJournal of Virology, 2007