Role of Immunity and Vaginal Microbiome in Clearance and Persistence of Human Papillomavirus Infection

Abstract

Cervical cancer disproportionately affects women of reproductive age, with 80% of cases occurring in low- and middle-income countries. Persistent infection with high-risk human papillomavirus (HPV) genotypes has been described as the most common non-systemic biological risk factor for the development of cervical cancer. The mucosal immune system plays a significant role in controlling HPV infection by acting as the first line of host defense at the mucosal surface. However, the virus can evade host immunity using various mechanisms, including inhibition of the antiviral immune response necessary for HPV clearance. Pro-inflammatory cytokines and the vaginal microbiome coordinate cell-mediated immune responses and play a pivotal role in modulating immunity. Recently, diverse vaginal microbiome (associated with bacterial vaginosis) and genital inflammation have emerged as potential drivers of high-risk HPV positivity and disease severity in women. The potential role of these risk factors on HPV recurrence and persistence remains unclear. This article reviews the role of cellular or cytokine response and vaginal microbiome dysbiosis in the clearance, persistence, and recurrence of HPV infection.

Keywords: cellular; cytokines; human papillomavirus; inflammation; vaginal microbiota.

Figure 1

HPV infection cycle in the ectocervix of the female genital tract. (A) The HPV virus particles penetrate the stratified squamous epithelium through microabrasion. The virus particles infect the basal keratinocytes in the basement membrane and establish an infection, viral replication occurs, and the infected cells are transported up the epithelium. (B) Viral particles are taken up by dendritic cells that secrete T cells attracting pro-inflammatory cytokines and chemokines (IL-1 α, IL-1β, IL-6, TNF-α, IL-12), which may facilitate activation and recruitment of CD4+ T cells. CD4+ T cells recognise HPV antigen presented by the dendritic cells and (C) undergoes proliferation and differentiation into the effector T cell. (D) The effort T cells [which proliferate into HPV specific memory T cell and (E, F)cytotoxic CD8+ T cell] binds with the naïve B cells, which differentiate to HPV specific plasma cells and HPV specific memory Bcells. Activation of cellular and humoral immunity is associated with clearance of HPV infection.