Immunology of HPV Infection

Abstract

Human papillomavirus (HPV) infection in the genital tract is common in young sexually active individuals, the majority of whom clear the infection without overt clinical disease. However, most of those who develop benign lesions eventually mount an effective cell-mediated immune response and the lesions regress. Regression of anogenital warts is accompanied histologically by a CD4+ T cell-dominated Th1 response, and animal models support this and provide evidence that the response is modulated by antigen-specific CD4+ T cell-dependent mechanisms. Failure to develop effective CMI 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 and activation of adaptive immune responses seem to be the hallmark of HPV infections. The viral infectious cycle is exclusively intraepithelial, there is no viraemia, no virus-induced cytolysis or cell death and viral replication, and release is not associated with inflammation. HPV globally downregulates the innate immune signalling pathways in the infected keratinocyte, pro-inflammatory 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 the 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.

Why Human Papillomavirus Acute Infections Matter

“…The immunology of HPV infections has been thoroughly reviewed elsewhere (e.g., [ 41 ]). We know that HPV infections concur with a local anti-inflammatory environment, and that although the adaptive immune response is very efficient at clearing the infection, its activation is variable and sometimes insufficient to prevent future re-infections [ 36 , 41 , 42 ].…”

Cytokine response following perturbation of the cervicovaginal milieu during HPV genital infection

“…They can also alter host gene expression (such as chemokines, adhesion molecules, and TLRs) or impair protein function and trafficking by dysregulating keratinocyte interferon (IFN) response and other antiviral pathways. [7][8][9] Additionally, interference with antigen processing in HPV infections has been described and can contribute to impeding detection of infected keratinocytes by cytotoxic T cells. [10] Most HPVs studies focus on chronic infections and cancer and there is a pronounced lack of data for non-persistent (also called "incident") infections.…”

Natural history, dynamics, and ecology of human papillomaviruses in genital infections of young women: protocol of the PAPCLEAR cohort study

“…Some factors have been shown to correlate with persistence (eg, immunosuppression, smoking and co-infection with other STIs16) but we do not know how these affect viral kinetics. Also, some changes in the interactions between virus and the host immunity appear to be related to persistence and disease progression17–20 but, again, we do not know the underlying interactions between the viruses, the host target cells, and the immune response in acute infections 12. Finally, it has been argued that the vaginal microbiota may differ between HPV-infected and HPV-uninfected women21 and that specific microbiota composition may interact with HPV detection 22.…”