Immune modulation by the hepatitis C virus core protein.

Hepatitis C virus (HCV) infection is currently the most important cause of chronic viral hepatitis in the world and one of the most frequent indications for liver transplantation. HCV uses different strategies to evade the innate and adaptive immune response, and this evasion plays a key role in determining viral persistence. Several HCV viral proteins have been described as immune modulators. In this review, we will focus on the effect of HCV nucleocapsid core protein in the function of immune cells and its correlation with the findings observed in HCV chronically infected patients. Effects on immune cell function related to both extracellular and intracellular HCV core localization will be considered. This review provides an updated perspective on the mechanisms involved in HCV evasion related to one single HCV protein, which could become a key tool in the development of new antiviral strategies able to control and/or eradicate HCV infection.

The effects of hepatitis C virus core protein on functional responses in the NK cell line YTS.

Hepatitis C virus infection affects more than 170 million people worldwide. More than 80% of the patients are not able to eliminate the virus and progress to a chronic infection that usually culminates in complications such as cirrhosis and/or hepatocellular carcinoma. Although the adaptive immune response has been widely shown to be essential for viral clearance, the role of natural killer (NK) cells is not clearly understood. In this study, the effect of HCV core protein is examined on NK cell function, i.e., cytotoxicity and cytokine secretion. The expression of core protein in the YTS NK cell line led to an increase in the percentage of apoptotic cells soon after transduction. The surviving cells exhibited decreased cytotoxicity associated with decreases in perforin and granzyme B expression. Furthermore, the HCV core protein-transduced YTS NK cells had reduced IFNγ production as well as an altered surface receptor expression pattern. These features may correspond to a state of functional anergy similar to that seen in T cells transduced with HCV core protein. Together, these data suggest that HCV core protein may alter NK cell function.

Ensayos de quimiosensibilidad en cultivos primarios de tumores cerebrales / Chemosensitivity test on brain tumors

Durante los últimos 50 años la quimioterapia (QT)ha jugado un importante papel en el tratamiento del cáncer. Sin embargo, el éxito o fracaso de nuevas drogas para un determinado tipo de cáncer es difícil de predecir. La quimio sensibilidad in vitro es un método atractivo para conocer a priori si ese tumor responderá a una pauta de QT y para determinar la dosis óptima de tratamiento en los enfermos con cáncer. Objetivo. Conocer la sensibilidad de tumores cerebrales frente a determinados fármacos antineoplásicos. Material y métodos. Se ensayaron 5 fármacos diferentes (carmustina, camptotecina, taxol, hidroxiureay tamoxifeno) en los cultivos primarios obtenidos de7 pacientes con glioblastoma multiforme, 15 pacientescon meningiomas y un paciente con medulo blastoma. Para estudiar la quimiosensibilidad se empleó el test del MTT, midiendo la densidad óptica por espectofotometríaa 450 nm. Resultados. Un total de 49 mediciones fueron realizadas, obteniendo 44 curvas dosis-respuesta válidas. Se emplearon concentraciones desde 10-2 M hasta 10-12 M para cada fármaco ensayado, obteniendo IC50 en cada caso como valor representativo de la sensibilidad del tumor a la droga. Conclusiones. El test MTT se muestra válido para medir la quimio sensibilidad in vitro de tumores cerebrales a nuevos fármacos

During last 50 years chemotherapy has played a very important part in the cancer treatment. However succes or failures of news drugs in one particular cancer its difficult to predict. In vitro chemo-sensitivity is an attractive method for knowing about responses of a tumor to ChT treatment and assess the best dose in the patient with cancer. Objective. To know brain tumors sensitivity againstantineoplastic drugs. Methods. Five differents drugs (carmustin, camptotecin, taxol, hydroxyurea and tamoxifen) were tested on short-term cultures from 7 patients with Glioblastoma multiforme, 15 patients with meningiomas and one patient with meduloblastoma. For testing chemosensitivity we used MTT assay, and we measured optic density by spectophotometry to 450 nm. Results. A total of 49 measurement were done, getting44 valids dose-result curves. For each drug we used from 10-2 M to 10-12 M gap, and IC50 result was representative of tumor sensitivity to the drug. Conclusion. our data support MTT assays like valid method for measuring in vitro chemosensitivity in brain tumors to news drugs

Hepatitis C virus core protein up-regulates anergy-related genes and a new set of genes, which affects T cell homeostasis.

Hepatitis C virus (HCV) infection is the main cause for chronic hepatitis, leading to cirrhosis and hepatic carcinoma. Virally induced immune dysfunction has been called as the cause for viral persistence. Previous results demonstrate that CD4 Jurkat cells stably expressing the HCV core protein show an increased activation of NFAT transcription factor and an impaired IL-2 promoter activity, affecting intracellular signaling pathways in a manner that mimics clonal anergy. We had shown previously that NFAT activates a transcriptional program, ensuing in immunological tolerance. In the present work, we have engineered lentiviral vectors expressing the HCV core to analyze the events, which unfold in the initial phase of HCV core-induced anergy. We show that genes initially described to be up-regulated by ionomycin-induced anergy in mice are also up-regulated in humans, not only by ionomycin but also by HCV core expression. We also show that HCV core is sufficient to cause NFAT nuclear translocation and a slow-down in cell-cycle progression, and using whole genome microarrays, we identify novel genes up-regulated in Jurkat cells expressing HCV core. The relevance of our results is highlighted by the presence of HCV in CD4 T cells from HCV chronically infected patients.