Human papillomavirus type 16 (HPV-16) has developed numerous ways to modulate host-initiated immune mechanisms. The HPV-16 E6 oncoprotein, for example, can modulate the cellular level, and consequently the activity, of procaspase 8, thus modifying the cellular response to cytokines of the tumor necrosis factor family. E6 from HPV-16, but not E6 from the low-risk types 6b and 11, alters the cellular level of procaspase 8 in a dose-dependent manner. Both the large and small (E6*) isoforms of E6, which originate by way of alternate splicing, can modulate procaspase 8 stability. Intriguingly, although both isoforms bind to procaspase 8, the large isoform accelerates the degradation of procaspase 8 while the small isoform stabilizes it. Binding leads to a change in the ability of procaspase 8 to bind either to itself or to FADD (Fas-associated death domain), with the large version of E6 able to inhibit this binding while the small isoform does not. Consistent with this model, knockdown of the large version of E6 by small interfering RNA leads to increases in the levels of procaspase 8 and its binding to both itself and FADD. Thus, these alternatively spliced isoforms can modulate both the level and the activity of procaspase 8 in opposite directions.High-risk types of human papillomaviruses (HPV) are causative agents in most cases of cervical carcinoma and are frequently implicated in head and neck cancers, as well. Much of the transforming ability of this virus can be attributed to the activities of its E6 and E7 oncoproteins. The HPV type 16 (HPV-16) E6 oncogene is an early gene expressed during HPV infection that plays an important role in cellular immortalization and transformation. The best-known activity of E6 is its ability to accelerate the degradation of p53 (50); however, not all of its transforming ability can be attributed to this activity (42,46,54,67), and E6 is known to influence additional cellular functions, such as the regulation of transcription and DNA replication (18,23,28,29,30,36,43,49,68,70), epithelial organization and differentiation (6,9,11,64), cell-cell adhesion, polarity and proliferation control (20,27,32,33,41,62,63), the DNA damage response (26, 55), and apoptotic pathways (15,16,21,61,66,67).Activation of the extrinsic apoptotic pathway begins with the binding of a signaling molecule, such as tumor necrosis factor (TNF), FasL, or TRAIL (TNF-related apoptosis inducing ligand), to its receptor. The resulting conformational change in the receptor then allows it to bind to additional adaptor and effector molecules (such as TRADD in the case of TNF and FADD [Fas-associated death domain] for TNF, FasL, and TRAIL) and ultimately results in the binding to and activation of the initiator caspase procaspase 8 (reviewed in references 47, 70, and 71). Activated caspase 8 can then activate caspase 3, which initiates the dissolution of a number of cellular proteins and structures and ultimately leads to apoptosis. Our previous work has shown that the HPV-16 E6 oncoprotein interacts with the extrin...

Human papillomavirus 16 is a causative agent of most cases of cervical cancer and has also been implicated in the development of some head and neck cancers. The early viral E6 gene codes for two alternatively spliced isoforms, E6 large and E6*. We have previously demonstrated the differential effects of E6 large and E6* binding on the expression and stability of procaspase 8, a key mediator of the apoptotic pathway. Additionally, we have reported that E6 binds to the FADD death effector domain (DED) at a novel E6 binding domain. Sequence similarities between the FADD and procaspase 8 DEDs suggested a specific region for E6 large /procaspase 8 binding, which was subsequently confirmed by mutational analysis as well as by the ability of peptides capable of blocking E6/FADD binding to also block E6 large /caspase 8 binding. However, the binding of the smaller isoform, E6*, to procaspase 8 occurs at a different region, as deletion and point mutations that disrupt E6 large /caspase 8 DED binding do not disrupt E6*/caspase 8 DED binding. In addition, peptide inhibitors that can block E6 large /procaspase 8 binding do not affect the binding of E6* to procaspase 8. These results demonstrate that the residues that mediate E6*/procaspase 8 DED binding localize to a different region on the protein and employ a separate binding motif. This provides a molecular explanation for our initial findings that the two E6 isoforms affect procaspase 8 stability in an opposing manner.The relationship between viruses and cancers is reflected in the observation that viral infections account for approximately 10 to 15% of the cancer burden worldwide (6, 60). This makes viral infections one of the preventable risk factors of cancer. Viruses are associated with several human malignancies, including hepatitis B and C virus-associated hepatocellular carcinomas (48), Epstein-Barr virus-associated nasopharyngeal carcinomas and lymphomas (36), and human T-cell leukemia virus-associated adult T-cell leukemia (8, 28). Although there is a correlation between infection and the onset of cancer, the frequency of infection supersedes the incidence of cancer inception, suggesting that the presence of the virus alone is not sufficient to trigger carcinogenesis. Progression from viral infection to tumor development therefore requires additional environmental and cellular factors in addition to the expression and activity of virus-encoded proteins (40).High-risk strains of human papillomavirus (HPV) (high-risk HPV [HR-HPV]) such as HPV16 and HPV18 have been implicated in most cases of cervical cancer and also in a subset of head and neck cancers (24,26,39). Infection with oncogenic strains of HPV represents up to 75% of all infections. Furthermore, 1/10 of all deaths among women worldwide can be attributed to HR-HPV-related cancers (44, 45). The key players in promoting cell transformation and immortalization following HPV infection are the viral early proteins E6 and E7. These proteins are well known for their ability to interact with the tumor suppressor...

Human papillomaviruses (HPVs) are small, double-stranded DNA viruses that preferentially infect epithelial tissues of the genital tract, hands, and feet (25, 42). The high-risk strains, in particular types 16 and 18, are closely associated with most incidences of cervical cancer, currently the second most common cancer and the fifth leading cause of cancer-related deaths among women worldwide (8, 38). High-risk strains are present in greater than 90% of cervical cancer cases (over half of these cases being positive for HPV-16) and have also been implicated in head and neck squamous cell carcinomas (16,28).

Oral administration of autoantigens and allergens can delay or suppress clinical disease in experimental autoimmune and allergic disorders. However, repeated feeding of large amounts of the tolerogens is required over long periods and is only partially effective in animals systemically sensitized to the ingested antigen. Enhanced suppression of type 1 autoimmune diabetes insulitis and hyperglycemia was demonstrated in both naive and immune animals following oral inoculation with plant-based antigens coupled to the cholera toxin B subunit (CTB). Thus, plant-synthesized antigens linked to the CTB adjuvant, can enhance suppression of inflammatory TH1 lymphocyte-mediated autoreactivity in both naive and immune animals. To stimulate adjuvant-autoantigen fusion protein biosynthesis in the gut mucosae, the authors evaluated oral inoculation of juvenile non-obese diabetic (NOD) mice with recombinant vaccinia virus (rVV) expressing fusion genes encoding CTB linked to the pancreatic islet autoantigens proinsulin (INS) and a 55-kDa C-terminal peptide from glutamate decarboxylase (GAD55). Hyperglycemia in both rVV-CTB:: INS and rVV-CTB:: GAD inoculated mice was substantially reduced in comparison with the uninoculated mouse control. Oral inoculation with rVV carrying the CTB::INS fusion gene generated a significant reduction in insulitis. An increase in IgG1 in comparison with IgG2c antibody isotype titers in rVV-CTB::INS infected mice suggested possible activation of autoantigen specific Th2 lymphocytes. The experimental results demonstrate feasibility of using vaccinia virus oral delivery of adjuvanted autoantigens to the mucosae of prediabetic mice for suppression and therapy of type 1 autoimmune diabetes.

In order to map antigenically important regions of glycoprotein B (gB) of pseudorabies virus (PrV), a panel of recombinant fragments of gB expressed in E. coli and truncated fragments of gB generated by cleavage of purified native gB with trypsin and cyanogen bromide was analysed by using 26 monoclonal antibodies directed against gB. Three continuous epitopes were localized in the vicinity of the N terminus of gB, between amino acids (aa) 59 and 126. One continuous epitope mapped between residues 214 and 279. The residues involved in the assembly of eight discontinuous epitopes were located between aa 540 and 734. The constituents of two discontinuous epitopes were harboured in a segment encompassing aa 540-646. The clustering of continuous epitopes at the extreme N terminus of PrV gB and the locations of residues involved in the assembly of discontinuous epitopes of PrV gB are in good agreement with data on epitope locations in gB homologues from other herpesviruses.