HPV innate immunity

Abstract

HPV infections of the epidermis and anogenital tract occur frequently in healthy individuals, and 'high risk' HPV types are a major risk factor for cervical cancer. The first line of defense against HPV is the innate immune system, which provides non specific protection against a variety of pathogens and also enhances the adaptive immune response. However, HPV-infected cells often evade innate immune recognition and elimination. HPV gene expression and release of virus occur in superficial squamous cells where virus antigens are not readily detected, and keratinocytes are not lysed during HPV infection so there is no inflammatory response. In addition, HPV early proteins inhibit specific components of the innate immune system. E6 and E7 inhibit signaling by type I interferons and decrease expression of multiple interferon-inducible genes. E5 and E7 inhibit expression of major histocompatibility complex class I proteins on the cell surface. HPV-infected cells are resistant to lysis by natural killer (NK) cells, but are sensitive to cytokine-activated NK cells. Activated macrophages also kill HPV-infected cells and control malignant development. Thus, innate immunity is important for prevention of HPV infections, but HPV often persists due to evasion or inactivation of innate defenses.

Cervical cancer cell lines expressing NKG2D-ligands are able to down-modulate the NKG2D receptor on NKL cells with functional implications

“…Human papillomavirus (HPV) infection is the most important risk factor for cervical cancer development [2,3]; persistence of high-risk HPV infection leads to premalignant lesions and may ultimately lead to cervical cancer in a multistep process [4,5]. The first line of defense against HPV in early infection is the innate immune system, which plays a crucial role in viral clearance [6]. …”

Prophylactic and Therapeutic Vaccines against Human Papillomavirus Infections

“…First, HPV infects cells in a damaged epithelium. cells [46]. Later, when the new viral proteins are produced, these proteins can be taken up by antigen-presenting cells (APCs), such as Langerhans cells or dendritic cells (DCs) [47].…”

Hepatitis B Surface Antigen-based Vaccines for Human Neoplastic Disease

“…HPV infection tends towards a tolerising response to HPV antigens (Doan et al, 1999), a result of immunosuppressive activities of E6 and E7 oncoproteins (Ronco et al, 1998;Park et al, 2000;Nees et al, 2001) that inhibit the innate immune response (Woodworth et al, 1992;Woodworth & Simpson, 1993;Stark et al, 1998), in turn compromising adaptive cellular immunity to HPV antigens by inhibition or inducing dysfunctional inflammatory responses (Evans et al, 2001;Lee et al, 2001;Guess & McCance, 2005;Mazibrada et al, 2008;15 Caberg et al, 2009;Lepique et al, 2009). Specific and chronic inflammation is associated with cervical carcinoma, the exact role of which is unknown (reviewed by Woodworth, 2002). The inflammatory profile, as a result of HPV infection, may contribute to lesional progression and the establishment of carcinoma (Giannini et al, 2002).…”

“…Persistence of viral infection and neoplasia, developing to squamous cell carcinoma, is a result of E6 and E7 oncogene expression. E6 and E7 work synergistically to restrain cells from cell cycle arrest and they interfere with the initial stages of innate and adaptive immune responses Woodworth, 2002;Wise-Draper & Wells, 2008). E6 and E7 expression is low and tightly regulated within basal keratinocytes during neoplastic development.…”

“…and E7 functions, which interfere with cell cycle, is immortalisation of the infected cell (zur Hausen, 1996) as well as interference with adaptive and innate immune responses (Park et al, 2000;Nees et al, 2001;Tindle, 2002;Woodworth, 2002;Frazer, 2009).…”