The Use of Both Therapeutic and Prophylactic Vaccines in the Therapy of Papillomavirus Disease

Human papillomavirus (HPV) is the most common sexually transmitted virus. The high-risk HPV types (i.e., HPV16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59) are considered to be the main etiological agents of genital tract cancers, such as cervical, vulvar, vaginal, penile, and anal cancers, and of a subset of head and neck cancers. Three prophylactic HPV vaccines are available that are bivalent (vs. HPV16, 18), tetravalent (vs. HPV6, 11, 16, 18), and non-avalent (vs. HPV6, 11, 16, 18, 31, 33,45, 52, 58). All of these vaccines are based on recombinant DNA technology, and they are prepared from the purified L1 protein that self-assembles to form the HPV type-specific empty shells (i.e., virus-like particles). These vaccines are highly immunogenic and induce specific antibodies. Therapeutic vaccines differ from prophylactic vaccines, as they are designed to generate cell-mediated immunity against transformed cells, rather than neutralizing antibodies. Among the HPV proteins, the E6 and E7 oncoproteins are considered almost ideal as targets for immunotherapy of cervical cancer, as they are essential for the onset and evolution of malignancy and are constitutively expressed in both premalignant and invasive lesions. Several strategies have been investigated for HPV therapeutic vaccines designed to enhance CD4+ and CD8+ T-cell responses, including genetic vaccines (i.e., DNA/ RNA/virus/ bacterial), and protein-based, peptide-based or dendritic-cell-based vaccines. However, no vaccine has yet been licensed for therapeutic use. Several studies have suggested that administration of prophylactic vaccines immediately after surgical treatment of CIN2 cervical lesions can be considered as an adjuvant to prevent reactivation or reinfection, and other studies have described the relevance of prophylactic vaccines in the management of genital warts. This review summarizes the leading features of therapeutic vaccines, which mainly target the early oncoproteins E6 and E7, and prophylactic vaccines, which are based on the L1 capsid protein. Through an analysis of the specific immunogenic properties of these two types of vaccines, we discuss why and how prophylactic vaccines can be effective in the treatment of HPV-related lesions and relapse

Human Papillomavirus infections in cervical samples from HIV-positive women: evaluation of the presence of the nonavalent HPV genotypes and genetic diversity

Non-nonavalent vaccine (9v) Human papillomavirus (HPV) types have been shown to have high prevalence among HIV-positive women. Here, 1444 cervical samples were tested for HPV DNA positivity. Co-infections of the 9v HPV types with other HPV types were evaluated. The HPV81 L1 and L2 genes were used to investigate the genetic variability of antigenic epitopes. HPV-positive samples were genotyped using the HPVCLART2 assay. The L1 and L2 protein sequences were analyzed using a self-optimized prediction method to predict their secondary structure. Co-occurrence probabilities of the 9v HPV types were calculated. Non9v types represented 49% of the HPV infections; 31.2% of the non9v HPV types were among the low-grade squamous intraepithelial lesion samples, and 27.3% among the high-grade squamous intraepithelial lesion samples, and several genotypes were low risk. The co-occurrence of 9v HPV types with the other genotypes was not correlated with the filogenetic distance. HPV81 showed an amino-acid substitution within the BC loop (N75Q) and the FGb loop (T315N). In the L2 protein, all of the mutations were located outside antigenic sites. The weak cross-protection of the 9v types suggests the relevance of a sustainable and effective screening program, which should be implemented by HPV DNA testing that does not include only high-risk types

Early improvement of glycaemic control after virus clearance in patients with chronic hepatitis C and severe liver fibrosis: a cohort study

HCV has been recognized as the cause of chronic hepatitis C (CHC) since 1990. CHC is associated with progressive liver damage and extrahepatic conditions. Direct antiviral agents (DAAs), approved in 2014, have shown effectiveness in eradicating HCV in most patients. However, little is known about the effect of viral eradication on hepatic and extra-hepatic damage. We performed a historical cohort study of patients with HCV-related liver diseases who achieved SVR from March 2015 to October 2016 at INMI Lazzaro Spallanzani liver Unit in Rome (Italy). Repeated measures of glycaemia were analysed through a multilevel analysis framework to assess short time kinetics of blood glucose level at different times after therapy and for different levels of HCV viremia. The analysis included 205 patients. A model assessing temporal kinetics and variation of glycaemia according to HCV viremia provided evidence that blood glucose levels significantly dropped in patients with diabetes achieving SVR. Most of the variations occurred at 3-5 weeks of therapy (-17.96 mg/dL; p<0.001) and in coincidence with HCV clearance (-13.92 mg/dL; p<0.001). A weak, non-statistically significant reduction was observed in normoglycemic patients. Our study provides evidence that DAAs therapy may significantly improve glycaemic control in patients with CHC achieving SVR even when liver diseases are already established

THE CALCIUM-MODULATED PROTEINS, S100A1 AND S100B, AS POTENTIAL REGULATORS OF THE DYNAMICS OF TYPE III INTERMEDIATE FILAMENTS

The Ca2+-modulated, dimeric proteins of the EF-hand (helix-loop-helix) type, S100A1 and S100B, that have been shown to inhibit microtubule (MT) protein assembly and to promote MT disassembly, interact with the type III intermediate filament (IF) subunits, desmin and glial fibrillary acidic protein (GFAP), with a stoichiometry of 2 mol of IF subunit/mol of S100A1 or S100B dimer and an affinity of 0.5-1.0 µM in the presence of a few micromolar concentrations of Ca2+. Binding of S100A1 and S100B results in inhibition of desmin and GFAP assemblies into IFs and stimulation of the disassembly of preformed desmin and GFAP IFs. S100A1 and S100B interact with a stretch of residues in the N-terminal (head) domain of desmin and GFAP, thereby blocking the head-to-tail process of IF elongation. The C-terminal extension of S100A1 (and, likely, S100B) represents a critical part of the site that recognizes desmin and GFAP. S100B is localized to IFs within cells, suggesting that it might have a role in remodeling IFs upon elevation of cytosolic Ca2+ concentration by avoiding excess IF assembly and/or promoting IF disassembly in vivo. S100A1, that is not localized to IFs, might also play a role in the regulation of IF dynamics by binding to and sequestering unassembled IF subunits. Together, these observations suggest that S100A1 and S100B may be regarded as Ca2+-dependent regulators of the state of assembly of two important elements of the cytoskeleton, IFs and MTs, and, potentially, of MT- and IF-based activities

A large ongoing outbreak of hepatitis A predominantly affecting young males in Lazio, Italy; August 2016 - March 2017

The hepatitis A virus (HAV) is mainly transmitted through the faecal-oral route. In industrialized countries HAV infection generally occurs as either sporadic cases in travelers from endemic areas, local outbreak within closed/semi-closed population and as foodborne community outbreak. Recently, an increasing number of HAV infection clusters have been reported among young men-who-have-sex-with-men (MSM). The Lazio Regional Service for the epidemiology and control for infectious diseases (SeRESMI) has noticed an increase of acute hepatitis A (AHA) since September 2016. Temporal analysis carried out with a discrete Poisson model using surveillance data between January 2016 and March 2017 evidenced an ongoing outbreak of AHA that started at the end of August. Molecular investigation carried out on 130 out of 513 cases AHA reported until March 2017 suggests that this outbreak is mainly supported by an HAV variant which is currently spreading within MSM communities across Europe (VRD_521_2016). The report confirms that AHA is an emerging issue among MSM. In addition through the integration of standard (case based) surveillance with molecular investigation we could discriminate, temporally concomitant but epidemiologically unrelated, clusters due to different HAV variants. As suggested by the WHO, in countries with low HAV circulation, vaccination programmes should be tailored on the local epidemiological patterns to prevent outbreaks among high risk groups and eventual spillover of the infection in the general population

A large ongoing outbreak of hepatitis A predominantly affecting young males in Lazio, Italy; August 2016 - March 2017

The hepatitis A virus (HAV) is mainly transmitted through the faecal-oral route. In industrialized countries HAV infection generally occurs as either sporadic cases in travelers from endemic areas, local outbreak within closed/semi-closed population and as foodborne community outbreak. Recently, an increasing number of HAV infection clusters have been reported among young men-who-have-sex-with-men (MSM). The Lazio Regional Service for the epidemiology and control for infectious diseases (SeRESMI) has noticed an increase of acute hepatitis A (AHA) since September 2016. Temporal analysis carried out with a discrete Poisson model using surveillance data between January 2016 and March 2017 evidenced an ongoing outbreak of AHA that started at the end of August. Molecular investigation carried out on 130 out of 513 cases AHA reported until March 2017 suggests that this outbreak is mainly supported by an HAV variant which is currently spreading within MSM communities across Europe (VRD_521_2016). The report confirms that AHA is an emerging issue among MSM. In addition through the integration of standard (case based) surveillance with molecular investigation we could discriminate, temporally concomitant but epidemiologically unrelated, clusters due to different HAV variants. As suggested by the WHO, in countries with low HAV circulation, vaccination programmes should be tailored on the local epidemiological patterns to prevent outbreaks among high risk groups and eventual spillover of the infection in the general population

Epstein-Barr Virus Stimulates Torque Teno Virus Replication: A Possible Relationship to Multiple Sclerosis

Viral infections have been implicated in the pathogenesis of multiple sclerosis. Epstein-Barr virus (EBV) has frequently been investigated as a possible candidate and torque teno virus (TTV) has also been discussed in this context. Nevertheless, mechanistic aspects remain unresolved. We report viral replication, as measured by genome amplification, as well as quantitative PCR of two TTV-HD14 isolates isolated from multiple sclerosis brain in a series of EBV-positive and -negative lymphoblastoid and Burkitt's lymphoma cell lines. Our results demonstrate the replication of both transfected TTV genomes up to day 21 post transfection in all the evaluated cell lines. Quantitative amplification indicates statistically significant enhanced TTV replication in the EBV-positive cell lines, including the EBV-converted BJAB line, in comparison to the EBV-negative Burkitt's lymphoma cell line BJAB. This suggests a helper effect of EBV infections in the replication of TTV. The present study provides information on a possible interaction of EBV and TTV in the etiology and progression of multiple sclerosis

Joining S100 proteins and migration:for better or for worse, in sickness and in health

The vast diversity of S100 proteins has demonstrated a multitude of biological correlations with cell growth, cell differentiation and cell survival in numerous physiological and pathological conditions in all cells of the body. This review summarises some of the reported regulatory functions of S100 proteins (namely S100A1, S100A2, S100A4, S100A6, S100A7, S100A8/S100A9, S100A10, S100A11, S100A12, S100B and S100P) on cellular migration and invasion, established in both culture and animal model systems and the possible mechanisms that have been proposed to be responsible. These mechanisms involve intracellular events and components of the cytoskeletal organisation (actin/myosin filaments, intermediate filaments and microtubules) as well as extracellular signalling at different cell surface receptors (RAGE and integrins). Finally, we shall attempt to demonstrate how aberrant expression of the S100 proteins may lead to pathological events and human disorders and furthermore provide a rationale to possibly explain why the expression of some of the S100 proteins (mainly S100A4 and S100P) has led to conflicting results on motility, depending on the cells used. © 2013 Springer Basel

Hepatitis E in Italy : 5 years of national epidemiological, virological and environmental surveillance, 2012 to 2016

Increasing numbers of hepatitis E cases are being reported in several European countries, including Italy, but the burden of hepatitis E virus (HEV) infection is largely unknown in the latter. To gain a better understanding of HEV epidemiology at national level in Italy, we piloted a strengthened and integrated human (epi-demiological and virological) and environmental HEV surveillance system between 2012 and 2016. Over the 5-year period, 169 confirmed hepatitis E cases were identified, with a national annual incidence of 0.72 cases per 1,000,000. Of 65 HEV-RNA positive samples of sufficient quality for molecular analysis, 66% were genotype HEV3, 32% HEV1 and 1% HEV4. The most frequent risk factor reported by all HEV3 infected cases, was the consumption of undercooked pork and sausage. For the environmental surveillance, 679 urban sewage samples were collected from 53 wastewater treatment plants and HEV-RNA was detected in 38/679 of the samples. Among these, 25 (66%) were genotype HEV3 and the remaining were HEV1. We demonstrate that autochthonous transmission and environmental circulation of genotype HEV3 is adding to travel-related HEV transmission in Italy. We recommend the \u2018One Health\u2019 approach to integrated surveillance, and to include HEV-related messages within health information campaigns focussing on food security