Dengue Hemorrhagic Fever at 60 Years: Early Evolution of Concepts of Causation and Treatment

Halstead, Scott B.; Cohen, Sanford N.

doi:10.1128/mmbr.00009-15

Cited by 76 publications

(58 citation statements)

References 56 publications

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“…However these are likely influenced by both specific host and viral factors that act in concert 5 . Severe disease has been associated with: secondary infection with a different serotype 6–8 , host genetic susceptibility 9 , patient co-morbidities 10,11 , specific DENV serotypes and genotypes 8,12–14 , viral load 15 and the immune response induced by the DENV-NS1 protein 16–19 .…”

Section: Introductionmentioning

confidence: 99%

The reintroduction of DENV-2 in 2011 in Panama and subsequent outbreak characteristic

et al. 2018

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The circulation of the South-east Asian/American (AS/AM) dengue 2 virus (DENV-2) genotype in the Americas has been associated with a high rate of severe disease. From 1993, the year DENV was reintroduced in Panama, until 2011 there were 29 dengue-associated deaths, 17 of which occurred in 2011, the most severe outbreak with a case fatality rate (CFR) of 44% (17 deaths out of 38 severe dengue cases). During this outbreak DENV-2 was reintroduced into the country, whereas over the prior five years DENV-1 and −3 were predominant. Herein, we describe the 2011 Panama outbreak and genetically characterize the Panamanian DENV-2 strains, which were associated with severe dengue disease in Panama. Our results suggest that the DENV-2 isolates from this outbreak belonged to the AS/AM genotype sub-clade 2BI and were genetically close to viruses described in the outbreaks in Nicaragua, Honduras, Guatemala and Mexico from 2006–2011. Sub-clade 2BI has previously been associated with severe disease in Nicaragua during outbreaks from 2005–2007.

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Section: Introductionmentioning

confidence: 99%

The reintroduction of DENV-2 in 2011 in Panama and subsequent outbreak characteristic

et al. 2018

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“…It was estimated that in 2015, 79.6 million dengue cases occurred in 196 countries 5 . Dengue is caused by any of the four antigenically distinct dengue virus serotypes (DENV1, DENV2, DENV3, and DENV4) and is transmitted to humans by the Aedes mosquitoes, the same vectors as for yellow fever virus, chikungunya virus, and Zika virus 1, 6, 7, 8, 9…”

Section: Introductionmentioning

confidence: 99%

Dengue virus serological prevalence and seroconversion rates in children and adults in Medellin, Colombia: implications for vaccine introduction

Carabalí

Lim

Velez

et al. 2017

International Journal of Infectious Diseases

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“…The latter may progress to hypovolemic shock (dengue shock syndrome [DSS]) (3,5). Among the four serotypes, DENV2 is the most prevalent on a global scale, followed by DENV3, DENV1, and DENV4 (6).…”

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confidence: 99%

Identification of a Pyridoxine-Derived Small-Molecule Inhibitor Targeting Dengue Virus RNA-Dependent RNA Polymerase

Colby-Germinario

Hassounah

et al. 2016

Antimicrob Agents Chemother

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The viral RNA-dependent RNA polymerase (RdRp) activity of the dengue virus (DENV) NS5 protein is an attractive target for drug design. Here, we report the identification of a novel class of inhibitor (i.e., an active-site metal ion chelator) that acts against DENV RdRp activity. DENV RdRp utilizes a two-metal-ion mechanism of catalysis; therefore, we constructed a small library of compounds, through mechanism-based drug design, aimed at chelating divalent metal ions in the catalytic site of DENV RdRp. We now describe a pyridoxine-derived small-molecule inhibitor that targets DENV RdRp and show that 5-benzenesulfonylmethyl-3-hydroxy-4-hydroxymethyl-pyridine-2-carboxylic acid hydroxyamide (termed DMB220) inhibited the RdRp activity of DENV serotypes 1 to 4 at low micromolar 50% inhibitory concentrations (IC 50s of 5 to 6.7 M) in an enzymatic assay. The antiviral activity of DMB220 against DENV infection was also verified in a cell-based assay and showed a 50% effective concentration (EC 50 ) of <3 M. Enzyme assays proved that DMB220 was competitive with nucleotide incorporation. DMB220 did not inhibit the enzymatic activity of recombinant HIV-1 reverse transcriptase and showed only weak inhibition of HIV-1 integrase strand transfer activity, indicating high specificity for DENV RdRp. S600T substitution in the DENV RdRp, which was previously shown to confer resistance to nucleoside analogue inhibitors (NI), conferred 3-fold hypersusceptibility to DMB220, and enzymatic analyses showed that this hypersusceptibility may arise from the decreased binding/incorporation efficiency of the natural NTP substrate without significantly impacting inhibitor binding. Thus, metal ion chelation at the active site of DENV RdRp represents a viable anti-DENV strategy, and DMB220 is the first of a new class of DENV inhibitor. D engue virus (DENV) belongs to the family Flaviviridae, a group of enveloped positive-sense single-stranded RNA viruses that includes the genera Hepacivirus (prototype, hepatitis C virus [HCV]), Flavivirus (prototype, yellow fever virus), and Pestivirus (prototype, bovine viral diarrhea virus) (1). Distinct from the hepaciviruses and pestiviruses that are not arthropodborne, the flaviviruses are transmitted by mosquitos and ticks. Dengue, the most prevalent arthropod-borne viral disease of humans, is caused by four serotypes (DENV1 to -4) and has had a major impact on global public health (2-4).Infection with any of the DENV serotypes may result in a wide spectrum of clinical symptoms ranging from a mild flu-like syndrome (known as dengue fever [DF]) to the most severe forms of the disease, which are characterized by coagulopathy, increased vascular fragility, and permeability (dengue hemorrhagic fever [DHF]). The latter may progress to hypovolemic shock (dengue shock syndrome [DSS]) (3, 5). Among the four serotypes, DENV2 is the most prevalent on a global scale, followed by DENV3, DENV1, and DENV4 (6). Dengue is endemic in over 100 tropical and subtropical countries, and the global incidence of dengue has grown ...

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Dengue Hemorrhagic Fever at 60 Years: Early Evolution of Concepts of Causation and Treatment

Cited by 76 publications

References 56 publications

The reintroduction of DENV-2 in 2011 in Panama and subsequent outbreak characteristic

The reintroduction of DENV-2 in 2011 in Panama and subsequent outbreak characteristic

Dengue virus serological prevalence and seroconversion rates in children and adults in Medellin, Colombia: implications for vaccine introduction

Identification of a Pyridoxine-Derived Small-Molecule Inhibitor Targeting Dengue Virus RNA-Dependent RNA Polymerase

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