High Levels of Plasma Dengue Viral Load during Defervescence in Patients with Dengue Hemorrhagic Fever: Implications for Pathogenesis

Wang, Wei‐Kung; Chao, Day Yu; Kao, Chuan-Liang; Wu, Han-Chung; Liu, Yung Ching; Li, Chien Ming; Lin, Shih Chung; Ho, Shih Ting; Huang, Jyh Hsiung; King, Chwan-Chuen

doi:10.1006/viro.2002.1704

Cited by 165 publications

(137 citation statements)

References 33 publications

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“…This difference in transmission and subsequent spread had been documented for other dengue virus genotypes (20), but the Southeast Asian genotype remains the only one directly linked to severe disease and displacement of another genotype. Since higher viremias have been associated with DHF (15,19,28,29), these results support the view that Southeast Asian viruses are more pathogenic and that more efficient virus replication in the primary target cells (the immature DCs which reside in the epidermis) provides a selective advantage over viruses of lower pathogenic potential. In the mosquito, infection proceeds through a large variety of cells and organs; our test for dissemination measures the end result of selection in this complex milieu but reflects the virus most probable to be transmitted to other humans.…”

Section: Discussionsupporting

confidence: 67%

Selection for Virulent Dengue Viruses Occurs in Humans and Mosquitoes

Cologna

Armstrong

Rico-Hesse

2005

J Virol

190

142

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Dengue is the most common mosquito-borne viral disease in humans. The spread of both mosquito vectors and viruses has led to the resurgence of epidemic dengue fever (a self-limited flu-like syndrome) and the emergence of dengue hemorrhagic fever (severe dengue with bleeding abnormalities) in urban centers of the tropics. There are no animal or laboratory models of dengue disease; indirect evidence suggests that dengue viruses differ in virulence, including their pathogenicities for humans and epidemic potential. We developed two assay systems (using human dendritic cells and Aedes aegypti mosquitoes) for measuring differences in virus replication that correlate with the potential to cause hemorrhagic dengue and increased virus transmission. Infection and growth experiments showed that dengue serotype 2 viruses causing dengue hemorrhagic fever epidemics (Southeast Asian genotype) can outcompete viruses that cause dengue fever only (American genotype). This fact implies that Southeast Asian genotype viruses will continue to displace other viruses, causing more hemorrhagic dengue epidemics.

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Section: Discussionsupporting

confidence: 67%

Selection for Virulent Dengue Viruses Occurs in Humans and Mosquitoes

Cologna

Armstrong

Rico-Hesse

2005

J Virol

190

142

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“…Studies that use PCR as an indicator for dengue virus detection show that viremia is higher in DHF versus DF patients. [30][31][32][33] Although antibody-virus complexes and neutralized virus would impact viral biological assays such as viral isolation, they would not likely impact PCR readouts.…”

Section: Discussionmentioning

confidence: 99%

Factors Influencing Dengue Virus Isolation by C6/36 Cell Culture and Mosquito Inoculation of Nested PCR-Positive Clinical Samples

Jarman

Nisalak

Anderson

et al. 2011

The American Society of Tropical Medicine and Hygiene

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Abstract. Dengue viral isolation is necessary for definitive diagnosis, pathogenesis and evolutionary research, vaccine candidates, and diagnostic materials. Using standardized techniques, we analyzed isolation rates of 1,544 randomly selected polymerase chain reaction (PCR)-positive samples, representing all four dengue serotypes, from patients with serologically confirmed dengue infections and evaluated whether clinical and laboratory results could be predictive of isolation using standard and mosquito isolation techniques. Viruses were isolated from 62.5% of the samples by direct application to C6/36 cells and increased to 79.4% when amplifying C6/36 negative samples by intrathorasic inoculation in Toxyrhynchites splendens mosquitoes. High viremia, measured by reverse transcriptase (RT)-PCR, was a strong predictor for viral isolation by either method. Isolation was most successful in samples collected early in the disease, had low antibody levels, temperatures greater than 38°C, and had a final clinical diagnosis of dengue fever. Dengue serotypes also played a role in the success of viral isolation.

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“…In humans, higher viremia is a defining feature of DHF/DSS compared to DF (35,56,57). In particular, DHF/DSS is associated with viremia that is 10-to 100-fold higher in titer than that of DF cases (4).…”

Section: Discussionmentioning

confidence: 99%

A Mouse-Passaged Dengue Virus Strain with Reduced Affinity for Heparan Sulfate Causes Severe Disease in Mice by Establishing Increased Systemic Viral Loads

Prestwood

Prigozhin

Sharar

et al. 2008

J Virol

106

135

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The four serotypes of dengue virus (DENV1 to DENV4) cause extensive morbidity and mortality. A major obstacle to studying disease pathogenesis and developing therapies has been the lack of a small-animal model. We previously reported isolation of a DENV2 strain, obtained by passaging a clinical isolate between mosquito cells and mice, that caused severe DENV disease in mice and contained multiple mutations, including many in domain II of the envelope (E) protein. Here, we describe a recombinant virus, differing from the non-mouse-passaged virus by two mutations in the E protein, that induces vascular leakage and tumor necrosis factor alpha (TNF-␣)-mediated lethality, while the non-mouse-passaged virus causes paralysis. This recombinant virus has a weaker affinity for heparan sulfate, resulting in an increased serum half-life, higher systemic viral loads, and high levels of TNF-␣ in the serum of infected mice. These results exemplify the role of the E protein in modulating virion clearance and connect the effect of clearance on the systemic viral loads responsible for severe disease manifestations.The four serotypes of dengue virus (DENV1 to DENV4) are the etiologic agents of dengue fever (DF) and dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS). DF is an acute, self-limited febrile illness. The more life-threatening DHF/DSS is characterized by a transient increase in vascular permeability, resulting in the leakage of plasma to the interstitium. DENV is transmitted to humans primarily by the mosquitoes Aedes aegypti and Aedes albopictus. It belongs to the Flaviviridae family and is related to the viruses that cause yellow fever (YFV), hepatitis C, and the West Nile (WNV), Japanese (JEV), and St. Louis encephalitides (5). DENV is an enveloped virus with a single-stranded, 10.7-kb, positive-sense RNA genome that is translated as a single polyprotein and cleaved into three structural proteins (C, prM/M, and E) and seven nonstructural (NS) proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5) by both viral and host proteases. At present, no effective antiviral therapy or vaccine exists. An estimated 2.5 billion people are at risk for DENV infection worldwide, and 50 million new cases of DF, 250,000 to 500,000 cases of DHF/DSS, and 25,000 deaths are reported per year (14,16).Despite the significant public health threat posed by DENV, the mechanisms of viral pathogenesis remain unclear. To better understand DENV disease, several mouse models have been developed. Mouse models of DENV infection include (i) intracerebral injection of suckling mice (50); (ii) mouse brainadapted DENV strains that rapidly induce encephalitis (12); (iii) A/J (20, 51) and AG129 (26, 52) mice that are infected with a high dose of a non-mouse-adapted DENV strain; (iv) chimeric SCID mice that are transplanted with either human peripheral blood mononuclear cells (58); CD34 ϩ cord blood cells (2), erythroleukemic K562 cells (36), or HepG2 hepatocarcinoma cells (1); and (v) chimeric RAG2 Ϫ/Ϫ ␥ c Ϫ/Ϫ mice transplanted with human fetal liver-de...

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High Levels of Plasma Dengue Viral Load during Defervescence in Patients with Dengue Hemorrhagic Fever: Implications for Pathogenesis

Cited by 165 publications

References 33 publications

Selection for Virulent Dengue Viruses Occurs in Humans and Mosquitoes

Selection for Virulent Dengue Viruses Occurs in Humans and Mosquitoes

Factors Influencing Dengue Virus Isolation by C6/36 Cell Culture and Mosquito Inoculation of Nested PCR-Positive Clinical Samples

A Mouse-Passaged Dengue Virus Strain with Reduced Affinity for Heparan Sulfate Causes Severe Disease in Mice by Establishing Increased Systemic Viral Loads

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