Host responses to infection with human papillomavirus

Abstract

Human papillomavirus (HPV) infections of cutaneous and genital mucosae are very common but the majority of individuals clear the infection without overt clinical disease. Those who develop lesions, also in most cases, mount an effective cell-mediated immune response and the lesions regress. The increased prevalence of HPV infections in individuals with a range of immunodeficiencies, including immunosuppression as a consequence of HIV infection, demonstrates the central importance of the CD4 T cell population in the control of established HPV infections. Failure to induce an effective immune response is related to inefficient activation of innate immunity and ineffective priming of the adaptive immune response; this defective immune response facilitates viral persistence, a key feature of high-risk HPV infection. This milieu becomes operationally HPV antigen tolerant, and the host's defences become irrevocably compromised. HPV antigen-specific effector cells are poorly recruited to the infected focus, and their activity is downregulated; neoplastic HPV-containing cervical keratinocytes expressing high levels of E6 and E7 oncoproteins are not killed in this immunosuppressive, tolerant milieu, and progression to high-grade disease and cancer can result. Highly efficacious prophylactic HPV L1 virus-like particle (VLP) vaccines circumvent viral epithelial evasion strategies since they are delivered by intramuscular injection. The stromal dendritic cells of the muscle that encounter the highly immunogenic repeat structure of the VLP then migrate with their cargo to the lymph node, initiating an immune cascade that results in a robust T cell-dependent B cell response, which generates high levels of L1-specific serum neutralizing antibodies and immune memory.