Biology of human papillomavirus infection and immune therapy for HPV-related head and neck cancers

Abstract

This article outlines the biology of human papillomavirus (HPV) infection of human mucosa and the cellular pathways that are altered through viral infection. The article provides a conceptual framework with which to understand the 2 major immunologic strategies to address HPV-related diseases: (1) prevention of primary HPV infection through the use of prophylactic vaccines and (2) treatment of established infection and diseases through therapeutic vaccines. Nonimmunologic therapy that targets cellular dysregulation induced by HPV infection is also discussed. The challenges in actualizing these conceptually attractive therapies on both a societal and biological level are examined.

Figure 1. HPV-16 Genome

The circular HPV-16 genome is 7904 base pairs and encodes six early (E) and two late (L) major proteins. The primary cellular targets of these proteins are indicated on the genome diagram: E6 ubiquitinates p53, E7 competes for binding with E2F to the hypophosphorylated “active” form of retinoblastoma tumor suppressor gene product (pRB), and E5 up-regulates epidermal growth factor receptor (EGFR).

Figure 2. Cell-mediated Immune Responses

Cell-mediated clearance of virally-infected cells begins with A) antigen presenting cells encountering viral particles or proteins. B) The virus is engulfed by the antigen presenting cell and undergoes intracellular degradation. C) The viral peptides are then presented to immature CD8+ T cells via MHC class I molecules. D) These activated cytotoxic CD8+ T cells then recognize and eliminate virally-infected epithelial cells.[78]

Figure 3. Mechanism of Preventative Vaccines in Inducing Humoral Immune Responses After Vaccination

The quadrivalent and bivalent HPV vaccines consist of the L1 capsid protein which self-assembles into virus-like particles (VLP). The humoral immune system is activated by the A) recognition of the virus-like particles (VLP) by a B cell surface immunoglobulin. B) The VLP is internalized and degraded into peptides, which C) are then presented to CD4+ Helper T cells via MHC class II molecules. D) An activated B cell then proliferates and differentiates into an antibody-secreting plasma cell. These circulating antibodies then recognize and bind HPV to prevent viral infection of an epithelial cell.[78]