The productive cycle of human papillomaviruses (HPVs) can be divided into discrete phases. Cell proliferation and episomal maintenance in the lower epithelial layers are followed by genome amplification and the expression of capsid proteins. These events, which occur in all productive infections, can be distinguished by using antibodies to viral gene products or to surrogate markers of their expression. Here we have compared precancerous lesions caused by HPV type 16 (HPV16) with lesions caused by HPV types that are not generally associated with human cancer. These include HPV2 and HPV11, which are related to HPV16 (supergroup A), as well as HPV1 and HPV65, which are evolutionarily divergent (supergroups E and B). HPV16-induced low-grade squamous intraepithelial lesions (CIN1) are productive infections which resemble those caused by other HPV types. During progression to cancer, however, the activation of late events is delayed, and the thickness of the proliferative compartment is progressively increased. In many HPV16-induced high-grade squamous intraepithelial lesions (CIN3), late events are restricted to small areas close to the epithelial surface. Such heterogeneity in the organization of the productive cycle was seen only in lesions caused by HPV16 and was not apparent when lesions caused by other HPV types were compared. By contrast, the order in which events in the productive cycle were initiated was invariant and did not depend on the infecting HPV type or the severity of disease. The distribution of viral gene products in the infected cervix depends on the extent to which the virus can complete its productive cycle, which in turn reflects the severity of cervical neoplasia. It appears from our work that the presence of such proteins in cells at the epithelial surface allows the severity of the underlying disease to be predicted and that markers of viral gene expression may improve cervical screening.

Human papillomavirus type 16 (HPV16) is an oncogenic virus that causes persistent infections in cervical epithelium. The chronic nature of HPV16 infections suggests that this virus actively evades the host immune response. Intraepithelial Langerhans cells (LC) are antigen-presenting cells that are critical in T-cell priming in response to viral infections of the skin. Here we show that HPV16 infection is directly associated with a reduction in the numbers of LC in infected epidermis. Adhesion between keratinocytes (KC) and LC, mediated by E-cadherin, is important in the retention of LC in the skin. Cell surface E-cadherin is reduced on HPV16-infected basal KC, and this is directly associated with the reduction in numbers of LC in infected epidermis. Expression of a single viral early protein, HPV16 E6, in KC reduces levels of cell surface E-cadherin thereby interfering with E-cadherin-mediated adhesion. Through this pathway, E6 expression in HPV16-infected KC may limit presentation of viral antigens by LC to the immune system, thus preventing the initiation of a cell-mediated immune response and promoting survival of the virus.Human papillomaviruses (HPV) cause persistent disease, despite producing immunogenic proteins throughout the replicative cycle. These viruses are therefore likely to possess an army of mechanisms to avoid the host immune system. Some types of HPV, in particular type 16, are strongly associated with the development of cancer after infections of the cervical epithelium (54). Consequently, the chronic nature of the infection, in association with high-risk oncogenic types of HPV, results in an increased risk of cellular transformation and malignancy.HPV is a nonlytic virus that is only permissive for viral replication in epidermal keratinocytes (KC). The ability of the virus to influence the immune system is therefore limited to the localized environment of the infected epidermis. Furthermore, activation of the adaptive immune response to HPV is dependent on cross-presentation of viral antigens to antigen-presenting cells (APC) resident in the skin (43). In the present study we explore the influence of HPV on the host's capacity to initiate the immune response by reducing numbers of APC resident at the site of infection.Langerhans cells (LC) are the epidermal contingent of the potent antigen-presenting dendritic cells (34) and constitute the primary APC in the skin. Immature LC form a contiguous network throughout the epithelium. Under steady-state conditions, CD14ϩ , E-cadherin-negative LC precursors migrate from the dermis into the epidermis in response to macrophage inflammatory protein 3␣ (MIP-3␣) (9) and differentiate into CD14ϩ , E-cadherin-positive immature LC when exposed to transforming growth factor ␤1 (TGF-␤1) (25). Both MIP-3␣ and TGF-␤1 are constitutively expressed by KC. Immature LC initiate migration from the epidermis in response to proinflammatory stimuli such as tumor necrosis factor alpha and interleukin-1␤ (12, 49). These cells become responsive to MIP-3␤, which directs the...

Background: Human papillomavirus (HPV), the causative agent of cervical cancer, can be screened for using self-collected vaginal samples (self-testing). This may overcome barriers to screening for Māori women who suffer a greater burden of cervical disease than New Zealand European women. Aims:This study aimed to explore the potential acceptability of HPV self-testing for never/under-screened (self-reported no cervical screen in 4+ years, aged 25+) Māori women by Kaupapa Māori (by, with and for Māori) mixed methods, involving hui (focus groups/interviews) and survey. Materials and Methods:Community-based researchers ran hui with women in four regions (N = 106) and supported hui participants to collect survey data (N = 397). Healthcare providers (HCPs) were also interviewed (N = 17). Hui data were thematically analysed. Survey data were analysed by age group, rural/urban, primary health organisation (PHO) enrolment, and time since last cervical screen.Results: Most survey participants were PHO-enrolled (87.15%) and attended regularly (71.79%), but did not attend regular cervical screening. A desire for bodily autonomy, including whakamā (embarrassment/shyness/reticence), was the most frequently cited barrier. Three in four women reported being likely/very likely to do an HPV self-test. Nine in ten women reported being likely/very likely to attend follow up if they receive a positive HPV test result. Women and HCPs in the hui emphasised the importance of health literacy, cultural competence and empathetic support. Conclusion:The findings indicate that with a culturally competent introduction of HPV self-testing, many currently never/under-screened Māori women would be willing to be screened and followed up if necessary. HPV self-testing has the potential to save lives. K E Y W O R D Scervical screening, HPV self-sampling, HPV self-testing, Indigenous health, Kaupapa Māori

Apoptotic cell death forms part of the host defense against virus infection. We tested orf virus, a member of the poxvirus family, for the ability to inhibit apoptosis and found that orf virus-infected cells were fully resistant to UV-induced changes in cell morphology, caspase activation, and DNA fragmentation. By using a library of vaccinia virus-orf virus recombinants, we identified an orf virus gene (ORFV125) whose presence was linked with the inhibition of apoptosis. The 173-amino-acid predicted protein had no clear homologs in public databases other than those encoded by other parapoxviruses. However, ORFV125 possessed a distinctive C-terminal domain which was necessary and sufficient to direct the protein to the mitochondria. We determined that ORFV125 alone could fully inhibit UV-induced DNA fragmentation, caspase activation, and cytochrome c release and that its mitochondrial localization was required for its antiapoptotic function. In contrast, ORFV125 did not prevent UV-induced activation of c-Jun NH 2 -terminal kinase, an event occurring upstream of the mitochondria. These features are comparable to the antiapoptotic properties of the mitochondrial regulator Bcl-2. Furthermore, bioinformatic analyses revealed sequence and secondary-structure similarities to Bcl-2 family members, including characteristic residues of all four Bcl-2 homology domains. Consistent with this, the viral protein inhibited the UV-induced activation of the proapoptotic Bcl-2 family members Bax and Bak. ORFV125 is the first parapoxvirus apoptosis inhibitor to be identified, and we propose that it is a new antiapoptotic member of the Bcl-2 family.

Background Indigenous women in the high‐income countries of Canada, Australia, New Zealand and USA, have a higher incidence and mortality from cervical cancer than non‐Indigenous women. Increasing cervical screening coverage could ultimately decrease cervical cancer disparities. Aims To increase cervical screening for under‐screened/never‐screened Māori women. Materials and Methods This study was a cluster randomised controlled trial. Inclusion criteria were women aged 25–69, last screened ≥4 years ago, in Northland, New Zealand. The intervention arm was the offer of a human papilloma virus (HPV) self‐test and the control arm was the usual offer of standard care – a cervical smear. The primary outcome was rate of cervical screening in the intervention group compared to control in Māori, the Indigenous peoples of New Zealand. Six primary care clinics were randomly allocated to intervention or control. Results Of 500 eligible Māori women in the intervention arm, 295 (59.0%) were screened. Of 431 eligible Māori women in the control arm, 94 (21.8%) were screened. Adjusting for age, time since last screen, deprivation index, Māori women in the intervention arm were 2.8 times more likely to be screened than women in the control arm (95% CI: 2.4–3.1, P‐value <0.0001). Conclusions Offer of HPV self‐testing could potentially halve the number of under‐screened/never‐screened Māori women and decrease cervical morbidity and mortality. These results may be generalisable to benefit Indigenous peoples facing similar barriers in other high‐income countries.