Predictions versus high-throughput experiments in T-cell epitope discovery: competition or synergy?

Prediction methods as well as experimental methods for T-cell epitope discovery have developed significantly in recent years. High-throughput experimental methods have made it possible to perform full-length protein scans for epitopes restricted to a limited number of MHC alleles. The high costs and limitations regarding the number of proteins and MHC alleles that are feasibly handled by such experimental methods have made in silico prediction models of high interest. MHC binding prediction methods are today of a very high quality and can predict MHC binding peptides with high accuracy. This is possible for a large range of MHC alleles and relevant length of binding peptides. The predictions can easily be performed for complete proteomes of any size. Prediction methods are still, however, dependent on good experimental methods for validation, and should merely be used as a guide for rational epitope discovery. We expect prediction methods as well as experimental validation methods to continue to develop and that we will soon see clinical trials of products whose development has been guided by prediction methods.     

Are 20 human papillomavirus types causing cervical cancer?

In 2012, the International Agency for Research on Cancer concluded that there was consistent and sufficient epidemiological, experimental and mechanistic evidence of carcinogenicity to humans for 12 HPV types (HPV16, HPV18, HPV31, HPV33, HPV35, HPV39, HPV45, HPV51, HPV52, HPV56, HPV58 and HPV59) for cervical cancer. Therefore, these types were considered as 1A carcinogens. They all belong to the family of the α‐Papillomaviridae, in particular to the species α5 (HPV51), α6 (HPV56), α7 (HPV18, HPV39, HPV45, HPV59) and α9 (HPV16, HPV31, HPV33, HPV35, HPV52, HPV58). Less evidence is available for a thirteenth type (HPV68, α7), which is classified as a 2A carcinogen (probably carcinogenic). Moreover, seven other phylogenetically related types (HPV26, HPV53, HPV66, HPV67, HPV68, HPV70 and HPV73) were identified as single HPV infections in certain rare cases of cervical cancer and were considered possibly carcinogenic (2B carcinogens). Recently, Halec et al [7] demonstrated that the molecular signature of HPV‐induced carcinogenesis (presence of type‐specific spliced E6*| mRNA; increased expression of p16; and decreased expression of cyclin D1, p53 and Rb) was similar in cervical cancers containing single infections with one of the eight afore‐mentioned 2A or 2B carcinogens to those in cancers with single infections with group 1 carcinogens. Ninety six percent of cervical cancers are attributable to one of the 13 most common HPV types (groups 1 and 2A). Including the additional seven HPV types (group 2B) added 2.6%, to reach a total of 98.7% of all HPV‐positive cervical cancers. From recently updated meta‐analyses, it was shown that HPV68, HPV26, HPV66, HPV67, HPV73 and HPV82 were significantly more common in cancer cases than in women with normal cervical cytology, suggesting that for these HPV types, an upgrading of the carcinogen classification could be considered. However, there is no need to include them in HPV screening tests or vaccines, given their rarity in cervical cancers. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Negative colposcopic biopsy after positive human papilloma virus (HPV) DNA testing: false-positive HPV results or false-negative histologic findings?

We studied histologic examination-related factors contributing to false-negative colposcopic biopsy results. Patients positive for high-risk human papillomavirus (HPV) DNA with negative cervical histologic findings were identified between January 2002 and December 2003. Three additional H&E-stained levels were obtained when the original diagnosis was confirmed on review. Patients with atypical squamous cells of undetermined significance (ASC) Papanicolaou test results, positive HPV DNA results, and negative cervical histologic findings accounted for 4.5% of all ASC smears submitted for HPV DNA testing. Slides and tissue blocks were available for 95 cases; 4% had focal HPV infection or mild dysplasia. When deeper levels were examined, 31% had clinically significant lesions: HPV infection or cervical intraepithelial neoplasia (CIN) 1, 19%; CIN 2/3, 8%; and dysplasia, not otherwise specified, 3%. Of the remaining patients, follow-up revealed squamous abnormalities in 25%. About 5% of patients with positive HPV DNA results had a negative follow-up biopsy result. "False-negative" biopsies accounted for one third of cases. Additional levels should be obtained for discrepant results. Close follow-up is crucial when the initial biopsy result is negative because a small number of patients will have squamous abnormalities in subsequent studies.     

Chronic delta hepatitis: Is the prognosis worse when associated with hepatitis C virus and human immunodeficiency virus infections?

Eighty-six patients were followed for 6.5 years to study the epidemiological, virological, and histological course of chronic delta hepatitis and the relationship of this disease with HIV and HCV infection. Patients were classified into four groups according to simultaneous HCV and/or HIV infection: group 1, HDV infection (20 cases); group 2, HDV and HCV infection (11 cases); group 3, HDV and HIV infection (12 cases), and group 4, HDV, HCV, and HIV infection (43 cases). All but 14 patients were asymptomatic at presentation. Liver histology showed chronic active hepatitis in 53 cases and cirrhosis in 19 cases. During follow-up, 52 patients remained asymptomatic, 34 developed hepatic dysfunction, 28 died, and 1 received a liver transplant. Among the 28 patients who died, 4 had HDV infection; 3 HDV and HCV infection; 3 HDV and HIV infection; and 18 HDV, HCV, and HIV infection. Death was due to liver failure in 16 (57%), AIDS in 10 (36%), and was unrelated to liver disease in 2 (8%) cases. There results demonstrate that chronic delta hepatitis is a severe disease, especially among drug users with HIV and HCV infection. The high morbidity and mortality of chronic delta hepatitis justifies the use of antiviral therapy to modify the natural course of the disease. © 1996 Wiley-Liss, Inc.     

Screening for cervical neoplasia: A community-based trial comparing Pap staining, human papilloma virus testing, and the new bi-functional celldetect® stain

Although cytological screening for cervical neoplasia has lowered mortality rates, current screening methods are plagued by sub‐optimal sensitivity and/or specificity. The purpose of this study was to compare the performance of the new CellDetect® staining technology as a potential screening tool. This initial, non‐blinded study, utilized samples are taken at a community‐based clinic. The diagnostic results using CellDetect® were compared with the performance of Pap staining and human papilloma virus (HPV) testing on the same material, as well as the follow‐up biopsies. These data were statistically analyzed in terms of sensitivity, specificity, predictive value (N.P.V and P.P.V), and inter‐observer agreement. Bi‐functional CellDetect® staining revealed morphological details and tinctorial properties that permitted recognition of neoplasia even at low magnification. Performance‐wise, CellDetect® demonstrated non‐inferiority for all statistical parameters to both Pap and HPV tests. Importantly, superior sensitivity compared with Pap staining was observed, as well as higher specificity than HPV testing with near equivalent sensitivity. We conclude that CellDetect® is a promising approach to early detection of cervical cancer because of its bi‐functional capabilities that afford high sensitivity and specificity. The data suggest that this new methodology warrants further and more extensive clinical evaluation. Diagn. Cytopathol. 2012. © 2011 Wiley Periodicals, Inc.     

Concentration levels of IL-10 and TNFα cytokines in patients with human papilloma virus (HPV) DNA⁺ and DNA⁻ cervical lesions

The present study was performed to assess the immune response in women with human papilloma virus (HPV) DNA? and DNA? cervical lesions. Eighty women with cervical lesions (age range?=?25-70 years) and 20 healthy individuals (control group) were enrolled in the study. Lesions were cytologically classified into four groups: ASC-US (20), CINI (30), CINII-III (16), and cervical carcinoma (14) prior to HPV DNA detection. Estimation of interleukin (IL)-10 and tumor necrosis factor (TNF)-α levels in cervical secretions and serum of the studied patients was performed utilizing ELISA. PCR screening kits were used to detect HPV DNA in cervical smears obtained from the studied cases with the different lesions. IL-10 levels in cervical secretions of HPV DNA? were significantly greater than those from DNA? patients (i.e., 88.73 vs 24.00 pg/ml) and from controls (i.e., 88.73 vs 8.27 pg/ml) and the levels were higher in DNA? patients than in controls (i.e., 24.00 vs 8.27 pg/ml). In comparison, serum IL-10 levels in these patients did not significantly differ from control values (i.e., 13.69 vs 12.16 vs 9.99 pg/ml, respectively). TNFα levels in cervical secretions of the HPV DNA? and DNA? cases did not significantly differ from values for the controls (i.e., 12.18 vs 9.90 vs 7.90 pg/ml, respectively). Serum TNFα of these patients also did not differ significantly from controls (i.e., 11.59 vs 11.90 vs 10.83 pg/ml, respectively). The detected levels of IL-10 in cervical secretions of patients with HPV DNA? lesions was significantly higher than in their sera, while secretion TNFα levels were nominally greater than sera values. Lastly, higher levels of IL-10 were observed in secretions of 10-14 (71.4%) patients who had progressive cervical lesions (HSIL and cervical cancer stages) who were HPV DNA? than observed in 20 of 66 (30.0%) of DNA? patients with similar progressive lesions. In general, the higher levels of IL-10 than of TNFα suggested a potential down-modulation of tumor-specific immune responses to HPV-infected lesions. This phenomenon appears to provide a tumor 'progressive' microenvironment in these particular patients.     

Concentration levels of IL-10 and TNFα cytokines in patients with human papilloma virus (HPV) DNA+ and DNA− cervical lesions

The present study was performed to assess the immune response in women with human papilloma virus (HPV) DNA⁺ and DNA^? cervical lesions. Eighty women with cervical lesions (age range?=?25–70 years) and 20 healthy individuals (control group) were enrolled in the study. Lesions were cytologically classified into four groups: ASC-US (20), CINI (30), CINII-III (16), and cervical carcinoma (14) prior to HPV DNA detection. Estimation of interleukin (IL)-10 and tumor necrosis factor (TNF)-α levels in cervical secretions and serum of the studied patients was performed utilizing ELISA. PCR screening kits were used to detect HPV DNA in cervical smears obtained from the studied cases with the different lesions. IL-10 levels in cervical secretions of HPV DNA⁺ were significantly greater than those from DNA^? patients (i.e., 88.73 vs 24.00 pg/ml) and from controls (i.e., 88.73 vs 8.27 pg/ml) and the levels were higher in DNA^? patients than in controls (i.e., 24.00 vs 8.27 pg/ml). In comparison, serum IL-10 levels in these patients did not significantly differ from control values (i.e., 13.69 vs 12.16 vs 9.99 pg/ml, respectively). TNFα levels in cervical secretions of the HPV DNA⁺ and DNA^? cases did not significantly differ from values for the controls (i.e., 12.18 vs 9.90 vs 7.90 pg/ml, respectively). Serum TNFα of these patients also did not differ significantly from controls (i.e., 11.59 vs 11.90 vs 10.83 pg/ml, respectively). The detected levels of IL-10 in cervical secretions of patients with HPV DNA⁺ lesions was significantly higher than in their sera, while secretion TNFα levels were nominally greater than sera values. Lastly, higher levels of IL-10 were observed in secretions of 10–14 (71.4%) patients who had progressive cervical lesions (HSIL and cervical cancer stages) who were HPV DNA⁺ than observed in 20 of 66 (30.0%) of DNA^? patients with similar progressive lesions. In general, the higher levels of IL-10 than of TNFα suggested a potential down-modulation of tumor-specific immune responses to HPV-infected lesions. This phenomenon appears to provide a tumor ‘progressive’ microenvironment in these particular patients.     

Life history trade-offs in human growth: adaptation or pathology?

Human beings growing-up in adverse biocultural environments, including undernutrition, exposure to infection, economic oppression/poverty, heavy workloads, high altitude, war, racism, and religious/ethnic oppression, may be stunted, have asymmetric body proportions, be wasted, be overweight, and be at greater risk for disease. One group of researchers explains this as a consequence of "developmental programming" (DP). Another group uses the phrase "predictive adaptive response" (PAR). The DP group tends to view the alterations as having permanent maladaptive effects that place people at risk for disease. The PAR group considers the alterations at two levels of adaptation: (1) "short-term adaptive responses for immediate survival" and (2) "predictive responses required to ensure postnatal survival to reproductive age." The differences between the DP and PAR hypotheses are evaluated in this article. A life history theory analysis rephrases the DP versus PAR debate from disease or adaptation to the concept of "trade-offs." Even under good conditions, the stages of human life history are replete with trade-offs for survival, productivity, and reproduction. Under adverse conditions, trade-offs result in reduced survival, poor growth, constraints on physical activity, and poor reproductive outcomes. Models of human development may need to be refined to accommodate a greater range of the biological and cultural sources of adversity as well as their independent and interactive influences.     

Prior infections or defence priming: what determines the risk of trematode infections in amphipod hosts?

Parasitology Research - Inducible defences against parasites that are only activated when needed can mitigate the cost of immune or behavioural evasion of parasites. Priming of the immune system...     

Does Toll-like receptor 3 play a biological role in virus infections?

The Toll-like receptor (TLR) family functions to recognize conserved microbial and viral structures with the purpose of activating signal pathways to instigate immune responses against infections by these organisms. For example, in vitro studies reveal that the TLR3 ligand is a double-stranded RNA (dsRNA), a product of viral infections. From this observation, it has been proposed that TLR3 is likely an important first signal for virus infections. We approached this issue by investigating the role of TLR3 in four different infectious viral models (lymphocytic choriomeningitis virus (LCMV), vesicular stomatitis virus (VSV), murine cytomegalovirus (MCMV), and reovirus) and in TLR3 genetically deficient ((-/-)) mice. Our results indicate that TLR3 is not universally required for the generation of effective antiviral responses because the absence of TLR3 does not alter either viral pathogenesis or impair host's generation of adaptive antiviral responses to these viruses.     

Epidemiology of herpes simplex virus types 1 and 2 in Germany: what has changed?

Infections with herpes simplex virus (HSV) types 1 and 2 are widespread in all human populations and result in persistent and latent infections. HSV-1 is commonly responsible for orofacial, HSV-2 more likely causes genital lesions. Herpes genitalis is one of the most important sexually transmitted diseases; furthermore, there are severe diseases associated with HSV (e.g., encephalitis). Over the last years an increase in clinical manifestations of HSV has been reported, and HSV-1 has been increasingly discussed as causative agent of herpes genitalis. We retrospectively evaluated the laboratory results of our routine diagnostic service for HSV infections, looking for changes of HSV epidemiology in recent years. Specimens from 2,678 herpes patients were obtained between 1 January 1996 and 31 March 2002. Using cell culture, the presence of HSV was investigated in swabs taken from different body sites, and clinical data on HSV localization and type were evaluated. We found 345 patients positive for HSV-1 and 212 positive for HSV-2. Clinical data were available from 72.1% of the patients with HSV-1, and 61.3% of those with HSV-2 infection. In genital herpes HSV-1 was the causative agent in 20% of men and in 25% of women. In patients suffering from orofacial herpes HSV-2 was detected in 7% of men and in 4% of women. To evaluate the frequency of neurological HSV diseases, 2,406 cerebrospinal fluid samples (CSF) from 2,121 patients suspected of meningitis or encephalitis were tested for HSV DNA by the polymerase chain reaction. Among those patients, 120 showed CSF positive for HSV DNA. Serum surveys of HSV-1 and HSV-2 infection recently established in our region were compared to similar studies performed in Germany 25 years ago. We found that seroprevalences have not changed over the last 25 years and that neurological HSV diseases are rare. However, as in the USA, a significant percentage of herpes genitalis is caused by HSV-1 in Germany.