We compare the design mechanism of action and clinical efficacy of

We compare the design mechanism of action and clinical efficacy of two recently licensed paradigm shifting vaccines. 2 induce hyper-proliferative lesions of keratinizing skin commonly known as warts. These infections are almost universal in childhood. SNX-2112 Other HPV genotypes including HPV 6 and 11 induce warty lesions on mucosal surfaces which are SNX-2112 extremely common in young adults and are transmitted through sexual contact. A limited subset of about 10 so-called “high risk” HPVs transmitted through sexual contact can initiate warty or non-warty epithelial dysplastic changes at mucosal surfaces particularly in the genital tract [2]. Evidence of current or past infection with these HPV genotypes is found in the majority of sexually active individuals though only 1-2% of infections become chronic and can then induce over many years invasive squamous or adenosquamous cancer of genital epithelia particularly the cervix [3]. Nearly 100% of cervical cancers and a substantial proportion of other anogenital squamous cancers are associated with high risk HPV infections. HPV 16 and HPV 18 are the genotypes most commonly associated with anogenital cancer accounting for about 70% of cervical squamous Rabbit Polyclonal to TF2A1. cancers [4]. HPV 18 is associated more commonly with adeno- and adenosquamous cervical cancer. Cancers associated with infection with high risk HPV are found at other sites especially tonsillar crypt epithelium. Some HPVs of skin notably HPV 5 8 and 38 are associated with development of squamous cell skin cancer in patients with chronically impaired immune responses [5] and proliferative lesions induced by mucosal “low risk” HPV genotypes 6 and 11 are much larger and last longer in immunosuppressed patients [6]. These observations demonstrate that host immunity is necessary to control HPV infection. Papillomaviruses encode two structural proteins L1 and L2 and up to 8 non-structural proteins (Figure 1). Oncogenesis associated with high risk HPV infection occurs in association with high level expression of two non-structural proteins E6 and E7 which together delay differentiation and promote proliferation of epithelial cells. E7 binds to and inhibits the function of pocket proteins including Rb permitting cells to cycle and proliferate when no longer SNX-2112 in contact with the epithelial basement membrane while E6 enables replication of cells with damaged DNA by promoting ubiquitination and destruction of p53 [7]. Both proteins have other actions which destabilize host cell DNA. These proteins have similar actions in high and low risk HPV infections. Together the E6 and E7 proteins of HPV 16 expressed as transgenes in keratinocytes are sufficient to induce epithelial tumours in mouse skin [8]. The reason why only some HPV infections persist and why persisting high risk HPV infections can SNX-2112 transform cells remains uncertain. While immune suppression increases the risk of HPV persistence and malignant transformation of high risk HPV infections the majority of patients with persistent HPV infection SNX-2112 and cervical cancer have apparently normal innate humoral and SNX-2112 cellular adaptive immune systems though there is a suggestion that the adaptive cellular immune responses to HPV E2 E6 and/or E7 non-structural proteins may be impaired in patients with persisting HPV infection [9]. Malignant transformation is generally associated with integration of the HPV genome into cellular DNA and high level expression of E6 and E7 proteins. Little immune response to HPV nonstructural proteins is detected except in invasive cancer [10]. Immune response to the major L1 capsid protein which is the basis of current vaccines to protect against HPV infection is weak and not always observed during or after natural infection [11 12 Figure 1 The natural history of papillomavirus infection in the cervix. Infection results in expression of viral non-structural proteins inducing minor alterations to epithelial architecture (CIN 1). Infectious virions in the nucleus of superficial epithelial … Steps leading to development of HPV vaccines PVs are encapsidated in an icosahedral coat comprised of 360 copies of the L1 capsid protein arranged as 72 pentamers and a smaller but uncertain number of copies of the minor L2 protein [13]. Immune.