Dengue fever, a very old disease, has reemerged in the past 20 years with an expanded geographic distribution of both the viruses and the mosquito vectors, increased epidemic activity, the development of hyperendemicity (the cocirculation of multiple serotypes), and the emergence of dengue hemorrhagic fever in new geographic regions. In 1998 this mosquito-borne disease is the most important tropical infectious disease after malaria, with an estimated 100 million cases of dengue fever, 500,000 cases of dengue hemorrhagic fever, and 25,000 deaths annually. The reasons for this resurgence and emergence of dengue hemorrhagic fever in the waning years of the 20th century are complex and not fully understood, but demographic, societal, and public health infrastructure changes in the past 30 years have contributed greatly. This paper reviews the changing epidemiology of dengue and dengue hemorrhagic fever by geographic region, the natural history and transmission cycles, clinical diagnosis of both dengue fever and dengue hemorrhagic fever, serologic and virologic laboratory diagnoses, pathogenesis, surveillance, prevention, and control. A major challenge for public health officials in all tropical areas of the world is to devleop and implement sustainable prevention and control programs that will reverse the trend of emergent dengue hemorrhagic fever.

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Dengue and Dengue Hemorrhagic Fever

Dengue and dengue hemorrhagic fever.

FLAVIVIRUSES 1103 Background and Classification 1103 Structure and Physical Properties of the Virion 1104 Binding and Entry 1105 Genome Structure 1106 Translation and Proteolytic Processing 1107 Features of the Structural Proteins 1108 Features of the Nonstructural Proteins 1109 RNA Replication 1112 Membrane Reorganization and the Compartmentalization of Flavivirus Replication 1112 Assembly and Release of Particles from Flavivirus-infected Cells 1112 Host Resistance to Flavivirus Infection 1113

Flaviviridae :T he Viruses and Their Replication

Hepatitis C virus (HCV) afflicts more than 170 million people worldwide causing chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. The recent development of complete cell-culture systems for HCV has accelerated the pace of hepatitis research. Specifically, these techniques have provided new insights into the virus lifecycle that are reviewed here. This should pave the way for developing bespoke and effective antiviral therapies and vaccines. Exciting progress has recently been made in understanding the replication of hepatitis C virus, a major cause of chronic hepatitis, liver cirrhosis and hepatocellular carcinoma worldwide. The development of complete cell-culture systems should now enable the systematic dissection of the entire viral lifecycle, providing insights into the hitherto difficult-to-study early and late steps. These efforts have already translated into the identification of novel antiviral targets and the development of new therapeutic strategies, some of which are currently undergoing clinical evaluation.

Replication of hepatitis C virus

Infection with the hepatitis C virus (HCV) is a major cause of chronic liver disease. HCV is an enveloped plus-strand RNA virus closely related to flavi- and pestiviruses. The first cloning of the HCV genome, about 10 years ago, initiated research efforts leading to the elucidation of the genomic organization and the definition of the functions of most viral proteins. Despite this progress the lack of convenient animal models and appropriate in vitro propagation systems have hampered a full understanding of the way the virus multiplies. This review summarizes our current knowledge about HCV replication and describes attempts pursued in the last few years to establish efficient and reliable cell culture systems.

Replication of the hepatitis C virus

Association between NS3 and NS5 Proteins of Dengue Virus Type 2 in the Putative RNA Replicase Is Linked to Differential Phosphorylation of NS5

Processing of dengue virus type 2 polyprotein precursor NS3-NS4A-NS4B-NS5 could be mediated by the catalytically active NS3 protease domain and NS2B in trans at the dibasic sites NS3-NS4A and NS4B-NS5. Subcellular localization of the unprocessed precursor NS3-NS4A-NS4B-NS5 showed that it was confined to a distinct subcellular organelle in the cytoplasm, which was distinct from the distribution of the mature NS5.

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Processing and localization of Dengue virus type 2 polyprotein precursor NS3-NS4A-NS4B-NS5.

Synthesis and characterization of an infectious dengue virus type-2 RNA genome (New Guinea C strain)

Dengue virus type 2, a member of the family Flaviviridae, encodes a single polyprotein precursor consisting of 3391 amino acid residues that is processed to at least 10 mature proteins by host and viral proteases. The NS3 protein contains a domain commonly found in cellular serine proteinases that in cooperation with NS2B is involved in polyprotein processing. In addition, NS3 and NS5 proteins contain conserved motifs found in several RNA helicases and RNA-dependent RNA polymerases, respectively. Both enzymatic activities have been suggested to be involved in viral RNA replication. In this report, we demonstrate that the NS3 and NS5 proteins interact in vivo in dengue virus type 2-infected monkey kidney (CV-1) cells and in HeLa cells coinfected with recombinant vaccinia viruses encoding these proteins as shown by coimmunoprecipitations and immunoblotting methods. We also show by immunofluorescence, metabolic labeling, and two-dimensional peptide mapping that NS5 is a nuclear phosphoprotein and that phosphorylation occurs on serine residues at multiple sites. Furthermore, NS5 exists in differentially phosphorylated states in the nuclear and the cytoplasmic fractions, and only the cytoplasmic form of NS5 is found to coimmunoprecipitate with NS3, suggesting that differential phosphorylation may control the interaction between these proteins and its function in the viral RNA replicase.

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Luwen Zhang

Papers

Association between NS3 and NS5 Proteins of Dengue Virus Type 2 in the Putative RNA Replicase Is Linked to Differential Phosphorylation of NS5

Processing and localization of Dengue virus type 2 polyprotein precursor NS3-NS4A-NS4B-NS5.

Synthesis and characterization of an infectious dengue virus type-2 RNA genome (New Guinea C strain)

Association between NS3 and NS5 Proteins of Dengue Virus Type 2 in the