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Hepatitis C virus: kinetics and quasispecies evolution during anti-viral therapy. 丙型肝炎病毒:抗病毒治疗过程中的动力学和准种进化。

Forum (Genoa, Italy) Pub Date : 2000-01-01

S Zeuzem

{"title":"Hepatitis C virus: kinetics and quasispecies evolution during anti-viral therapy.","authors":"S Zeuzem","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>The balance of virus production and clearance for untreated patients with chronic hepatitis C changes into a decline of viraemia when initiating effective anti-viral treatment. During the first phase of interferon-alpha (IFN-a) therapy, the kinetics of the viral load is characterised by a rapid dose-dependent decline starting after a delay of about eight to nine hours. This early response can be observed for almost all patients treated with IFN-a. After about 24 to 48 hours, the viral decline slows down leading to a second phase with a relatively stable exponential decay. Some non-responding patients show a nearly constant viraemia and some even a rebound throughout this second phase. Kinetic models allow the estimation of rates of viral production and clearance and reveal high turnover rates of hepatitis C virus (HCV) and an in vivo half-life of hepatitis C virions of a few hours, only. Due to the continuous and high replication rate in vivo, the low fidelity of the ribonucleic acid (RNA)-dependent RNA polymerase, and the immune surveillance of the host, HCV exists in an individual patient as a heterogeneous population of related viruses (quasispecies). A high degree of quasispecies variability correlates with a lower response to IFN-a therapy. Changes of the quasispecies population are more pronounced after initiation of treatment with IFN-a or interleukin-12 than during the natural course of disease. Ribavirin, however, has not been found to affect the HCV quasispecies population. Identification of a specific region within an envelope-encoding gene as the most variable region of HCV and as a critical neutralisation domain suggests that viral escape mechanisms are a possible cause for chronification and poses a major challenge for the development of a broadly reactive vaccine against HCV.</p>","PeriodicalId":79489,"journal":{"name":"Forum (Genoa, Italy)","volume":"10 1","pages":"32-42"},"PeriodicalIF":0.0,"publicationDate":"2000-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21569222","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Control of dendritic cell migration by chemokines. 趋化因子对树突细胞迁移的控制。

Forum (Genoa, Italy) Pub Date : 1999-10-01

S Sozzani, A Mantovani, P Allavena

引用次数: 0

Lessons from gene modified mice. 基因改造小鼠的经验教训。

Forum (Genoa, Italy) Pub Date : 1999-10-01

S Lira

引用次数: 0

A new insight into the role of "old" chemotactic peptide receptors FPR and FPRL1: down-regulation of chemokine receptors CCR5 and CXCR4. 对“老”趋化肽受体FPR和FPRL1作用的新认识:趋化因子受体CCR5和CXCR4的下调

Forum (Genoa, Italy) Pub Date : 1999-10-01

Y Le, W Shen, B Li, W Gong, N M Dunlop, J M Wang

{"title":"A new insight into the role of \"old\" chemotactic peptide receptors FPR and FPRL1: down-regulation of chemokine receptors CCR5 and CXCR4.","authors":"Y Le, W Shen, B Li, W Gong, N M Dunlop, J M Wang","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>N-formyl peptides, such as fMet-Leu-Phe (fMLP), are some of the first identified and most potent chemoattractants for phagocytic leukocytes. In addition to the bacterial peptide fMLP and the putative endogenously produced formylated peptides, we recently identified a number of other novel peptide agonists that selectively activate the prototype formyl peptide receptor (FPR) and/or its variant FPRL1. These agonists include several synthetic peptide domains derived from the envelope proteins of the human immunodeficiency virus type 1 (HIV-1) and intact human acute phase serum protein serum amyloid A. The activation of FPR and/or FPRL1 in monocytes by these agonists resulted in increased cell migration, calcium mobilisation and the heterologous down-regulation of the expression and function of chemokine receptors, notably CCR5 and CXCR4, two crucial fusion co-receptors for HIV-1. This down-regulation of CCR5 by FPR and FPRL1 agonists was associated with a rapid serine phosphorylation of CCR5. The desensitisation of CCR5 by FPR or FPRL1 agonists, not only inhibited its biological function induced by chemokine ligands, but also interfered with its capacity to act as a fusion co-receptor for monocyte tropic HIV-1. Thus, heterologous desensitisation by FPR and FPRL1 may play an important role in orchestrating the host innate immune responses which generate multiple chemotactic stimulants. Furthermore, the understanding of the structural and biochemical basis of FPR/FPRL1 activation may lead to the development of novel immunoregulatory and anti-HIV agents that emulate the process of heterologous desensitisation.</p>","PeriodicalId":79489,"journal":{"name":"Forum (Genoa, Italy)","volume":"9 4","pages":"299-314"},"PeriodicalIF":0.0,"publicationDate":"1999-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21469649","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Evidence-based medicine and practice: what's new for the physicians? 循证医学与实践:医生有什么新发现?

Forum (Genoa, Italy) Pub Date : 1999-10-01

A Liberati, V Pistotti, E Telaro

引用次数: 0

Structure and function of the CC chemokine receptor (CCR) 8. CC趋化因子受体(CCR)的结构与功能

Forum (Genoa, Italy) Pub Date : 1999-10-01

M Napolitano, A Santoni

引用次数: 0

The role of chemokines in the immunopathology of pulmonary disease. 趋化因子在肺部疾病免疫病理中的作用。

Forum (Genoa, Italy) Pub Date : 1999-10-01

S L Kunkel, N W Lukacs, R M Strieter, S W Chensue

{"title":"The role of chemokines in the immunopathology of pulmonary disease.","authors":"S L Kunkel, N W Lukacs, R M Strieter, S W Chensue","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>During the last decade, our understanding of the mechanisms involved in the initiation and maintenance of pulmonary disease has been greatly aided by advances in the field of chemokine biology. Chemokines comprise four supergene families, two of these families (the CC and CXC chemokine groups) are quite large and contain over 50 identified ligands and at least 14 individual receptors. Two additional chemokine families (C, CXXXC chemokines) are small and contain lymphotactin and fractalkine, respectively, as their members. In addition to their originally identified chemotactic activity, chemokines possess a variety of biological activities, ranging from immunomodulating leukocyte activation to suppressing HIV infection. The latter effect is due to the ability of specific chemokine receptors to serve as co-receptor for HIV entry into specific leukocyte sub-populations. A number of in vitro and in vivo studies have underscored the importance of chemokine biology in the progression of both acute and chronic lung diseases. These investigations have demonstrated the importance of targeting chemokines for new therapeutic approaches to treat pulmonary disease. A variety of acute and chronic lung diseases have been shown to possess a chemokine component and contribute to the initiation and maintenance of lung pathology, thus, there is little doubt that a further understanding of the mechanisms of pulmonary diseases will rely upon advances in the field of chemokine biology.</p>","PeriodicalId":79489,"journal":{"name":"Forum (Genoa, Italy)","volume":"9 4","pages":"339-55"},"PeriodicalIF":0.0,"publicationDate":"1999-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21469654","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Neoadjuvant/primary chemotherapy in cancer treatment: what advantage? 新辅助/初级化疗在癌症治疗中的优势是什么?

Forum (Genoa, Italy) Pub Date : 1999-07-01

W Wynendaele, A T van Oosterom

引用次数: 0

Cancer vaccination. 癌症疫苗接种。

Forum (Genoa, Italy) Pub Date : 1999-07-01

M Del Vecchio, G Parmiani

引用次数: 0

Developing new anti-cancer drugs: novel targets and methodological problems. 开发新的抗癌药物:新的靶点和方法问题。

Forum (Genoa, Italy) Pub Date : 1999-07-01

V Spataro, C Sessa

{"title":"Developing new anti-cancer drugs: novel targets and methodological problems.","authors":"V Spataro, C Sessa","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>The identification of molecular events relevant in the biology of cancer cells and the possibility of defining the molecular profile of cancer cell lines have radically changed the process of cancer-drug development. Cancer drug discovery relies now mainly on the National Cancer Institute cell line screening program; this screening system allows the selection of compounds with well-defined molecular mechanisms of action by screening them on cell lines characterised at the molecular level and by comparing their cytotoxicity through a computer-based analysis of the response profile. Biologically targeted drugs, which should hit specific molecular or biochemical targets, can be classified by a specific target, such as farnesyltransferase inhibitors, or by general mechanism of action. The clinical development of these new anti-cancer agents presents a significant challenge because clinical studies should comply with the molecular premises and be devised in order to provide the \"proof of principle\", that is the ability of the drug to interact with and activate or block the molecular target. After a summary of the main features and problems faced in the clinical development of biologically targeted anti-cancer therapies, the pre-clinical and clinical data available for some cell-cycle modulators, signal transduction inhibitors, drugs acting on the mitochondria and proteasome inhibitors will be reviewed.</p>","PeriodicalId":79489,"journal":{"name":"Forum (Genoa, Italy)","volume":"9 3","pages":"200-9"},"PeriodicalIF":0.0,"publicationDate":"1999-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21367066","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

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