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PubMed2003

Behavior of the dengue virus in solution.

The dengue virus consists of four antigenically related but distinct viruses, termed Dengue virus 1-4 (DEN 1-4). We have established that the dengue virus loses infectivity over time in solution in an exponentially declining manner. The four strains examined (one from each serotype) have half-lives that range from 2.5 to 7.5 hr in defined medium. The half-life is temperature and pH-dependent and is affected by the nature of the host cell in which it is produced, but is not dependent upon the presence of either Mg(2+) ions or chelating agents. Electron microscopy (EM) of solutions of the dengue virus show almost complete virus aggregation after 24 hr at room temperature, while RT-PCR shows an intact RNA genome. These results show that the solution environment of the dengue virus is an important determinant of dengue virus infectivity.

Animals↗
PubMed1999

Rapid subtyping of dengue viruses by restriction site-specific (RSS)-PCR.

Dengue is a major public health problem worldwide. It is caused by four dengue virus serotypes, each further divided into distinct genetic subtypes. Strain typing is important for understanding the epidemiology and viral factors associated with disease transmission. However, most of the existing subtyping methods are expensive and technically unwieldy for timely, practical applications in developing countries. Here we describe a simple, rapid, PCR-based subtyping method, restriction site-specific (RSS)-PCR, which we used to analyze dengue virus serotypes 2 and 3. For each serotype, four primers targeted to sequences spanning polymorphic endonuclease restriction sites in the envelope gene were used to reverse transcribe and amplify viral RNA. These RT-PCR products generated distinct electrophoretic band patterns for different strains. Analysis of 73 dengue-2 strains and 54 dengue-3 strains representing a broad geographic distribution over several decades revealed that the RSS-PCR fingerprints reproducibly fell into 7 and 3 groups, respectively. These groups correlated well with previous phylogenetic classifications. This one-step assay should be widely accessible and allow more detailed epidemiologic investigations in dengue-endemic countries. This novel PCR approach to subtyping organisms based on restriction site polymorphisms should be applicable to other pathogens.

Dengue Virus↗
PubMed1994

Precise location of sequential dengue virus subcomplex and complex B cell epitopes on the nonstructural-1 glycoprotein.

The reactions of a panel of 34 mouse monoclonal antibodies (MAbs) specific for the dengue-2 virus nonstructural-1 glycoprotein (NS1), were analysed using 174 overlapping synthetic nonameric peptides covering the entire sequence. Using this methodology, four epitopes were identified. One pair of MAbs, which defined a dengue-2/4 virus subcomplex epitope (24C: amino acids 299-309) using native NS1 proteins, showed the same reaction pattern with synthetic peptides containing the corresponding NS1 sequences of each virus serotype. One amino acid substitution, present in the sequences from the dengue-1/3 virus subcomplex abrogated almost all reaction by these MAbs. A dengue complex epitope (LX1: amino acids 111-121) was also located and peptides containing the sequences of each serotype were shown to contain only antigenically silent amino-acid substitutions. In contrast, MAbs which defined a dengue type-specific epitope (LD2: amino acids 25-33) and another dengue subcomplex epitope (24A: amino acids 61-69) failed to show the same reaction profiles using peptides of each serotype, suggesting that these determinants were partially dependent upon conformation. The LX1 epitope is a good candidate for further trials aimed at generating cross-protective immune responses to these viruses without the risk of antibody-dependent enhancement.

Amino Acid Sequence↗
PubMed1995

Analysis of functional epitopes on the dengue 2 envelope (E) protein using monoclonal IgM antibodies.

Forty-two hybridomas secreting IgM antibody against dengue virus were derived from spleen cells of dengue 2 infected mice. Antibody from 27 of these recognised the E protein of this virus. Of the 22 antibodies which neutralised dengue 2, only two cross-reacted with other flaviviruses. These 22 antibodies recognised three discrete domains on dengue virions. Competitive binding studies with IgG monoclonal antibodies suggested that two of the three domains were recognised by both IgG and IgM antibodies and that there were two additional domains which may be recognised exclusively by either IgG or IgM antibodies. IgM antibodies reacting with domains recognised by IgG antibodies that enhanced infection of susceptible cells by dengue 2, had no enhancing properties. None of the IgM antibodies activated the serum complement system after reacting with dengue 2 virions.

Animals↗
PubMed1985

Fetal rhesus monkey lung cells can be grown in serum-free medium for the replication of dengue-2 vaccine virus.

Serum-free media were developed to grow diploid fetal rhesus monkey lung (DBS-FRhL-2) cells and to propagate dengue-type 2 virus vaccine strain PR-159 (dengue-2 vaccine virus). Vitamins, amino acids, growth factors, hormones and other organic compounds, and inorganic salts were substituted for fetal bovine serum. The composition of the medium that was optimal for growth of DBS-FRhL-2 cells differed from medium optimal for the propagation of dengue-2 vaccine virus. Insulin, epidermal growth factor, fibroblast growth factor, and platelet-derived growth factor were required for DBS-FRhL-2 cell proliferation in serum-free medium but were inhibitory for virus propagation. Adenosine, cytidine, guanosine, uridine, and thymidine, each at 0.01 mM concentration, were necessary as medium supplements to obtain a high yield of dengue-2 vaccine virus in DBS-FRhL-2 cells under serum-free conditions. DBS-FRhL-2 cells grown in serum-free medium produced dengue-2 vaccine virus with yields similar to those of cells grown in the presence of serum. Dengue-2 vaccine virus obtained under serum-free conditions retained its phenotypic markers such as temperature sensitivity and small plaque size.

Animals↗
PubMed1985

Quantity of dengue virus required to infect rhesus monkeys.

As part of a dengue vaccine study, it was necessary to determine how much virus was required to infect rhesus monkeys. Serial dilutions of dengue 2 and 4 viruses were inoculated subcutaneously into groups of five monkeys and seroconversions determined on days 30 and 60 post-inoculation. The viruses were also titrated simultaneously in LLC-MK2 cells and mosquitoes. It was calculated that 9.5 mosquito infectious doses 50 (MID50) of dengue 2 virus and 22 MID50 of dengue 4 virus were required to infect 50% of the monkeys. The data suggest that 100 MID50 of dengue virus should be used as a challenge dose for monkeys previously immunized with dengue vaccine.

Animals↗
PubMed1983

Genetic variation among dengue 2 viruses of different geographic origin.

Genetic variation in dengue 2 isolates from various geographic areas was examined by oligonucleotide fingerprinting of the 40 S genome RNA. Oligonucleotide maps of geographically isolated and epidemiologically unrelated viruses were very distinct. Direct comparison of the oligonucleotide map of the dengue 2 prototype New Guinea 2 virus, isolated in 1944, with the fingerprints of more recent isolates from the South Pacific indicated that the genome of dengue 2 virus had undergone extensive change although the viruses are serologically indistinguishable. The oligonucleotide map of an isolate from a recent case in Jamaica and a mosquito isolate from Upper Volta, Africa, were recognized to be almost identical, suggesting that virus may have been introduced into the Caribbean from West Africa. Likewise, the fingerprints of isolates from Puerto Rico and the South Pacific shared 80 to 95% of their large oligonucleotides, suggesting that the virus involved in these epidemics may have spread throughout Tahiti, American Samoa, Fiji, and to Puerto Rico in the Caribbean or vice versa. On the basis of these studies, five genetic variants or topotypes of dengue 2 virus have been established: (1) Puerto Rico-South Pacific, (2) Burma-Thailand, (3) the Seychelles, (4) the Philippines, and (5) Jamaica-West Africa. Oligonucleotide fingerprinting offers a highly sensitive and reproducible technical approach to the investigation of dengue 2 virus intratypic variation and possibly to the understanding of the biological variation associated with dengue fever and hemorrhagic disease.

Africa, Western↗
PubMed1986

Nucleotide sequence and deduced amino acid sequence of the structural proteins of dengue type 2 virus, Jamaica genotype.

The nucleotide sequence of the 5'-terminal 2469 bases of dengue 2 (Jamaica genotype) virus has been determined and the encoded proteins compared with those of yellow fever and West Nile viruses, which belong to different flavivirus serogroups. The cDNA clone which was sequenced contains a 5'-noncoding region of 96 nucleotides followed by a single open reading frame coding for the structural proteins 5'-C-prM(M)-E-3' and the beginning of the NS1 nonstructural protein. The amino acid sequence homology between the structural polyprotein precursor of dengue 2 virus and those of yellow fever and West Nile viruses is 36.5 and 42%, respectively. The dengue virus structural proteins are similar in size and composition to those of the other flaviviruses. The basic capsid protein and the membrane and envelope proteins have hydrophobic regions at their C termini. The dengue 2 capsid C, membrane M, and envelope E proteins share 13, 36, and 43% homology, respectively, with the cognate proteins of yellow fever virus, and 33, 32, and 47% homology with the cognate proteins of West Nile virus. All 6 cysteine residues in the dengue 2 premembrane protein and all 12 cysteine residues in the dengue 2 envelope protein are conserved in the cognate proteins of yellow fever and West Nile viruses.

Amino Acid Sequence↗
PubMed1987

The nucleotide sequence of dengue type 4 virus: analysis of genes coding for nonstructural proteins.

We recently cloned a full-length DNA copy of the dengue type 4 virus genome. Analysis of the 5' terminal nucleotide sequence suggested that the three-virion structural proteins are synthesized by proteolytic cleavage of a polyprotein precursor which is encoded in one open reading frame. We now present the remaining sequence of the dengue type 4 virus genome which codes for the nonstructural proteins. The entire genome, which is 10,644 nucleotides in length, contains one long open reading frame which codes for a single large polyprotein 3386 amino acids in length. Alignment of the dengue nonstructural protein sequence with that of other flaviviruses, including yellow fever and West Nile viruses, revealed that significant homology exists throughout the entire nonstructural region of the dengue genome and this allowed tentative assignment of individual nonstructural proteins in the following order: NS1, NS2a, NS2b, NS3, NS4a, NS4b, and NS5-COOH. Processing of the nonstructural proteins appears to involve two types of proteolytic cleavage: the first occurs after a long hydrophobic signal sequence and the second occurs at a junction between two basic amino acids and a small polar amino acid. A notable exception is the cleavage at the N-terminus of the dengue NS3 which may take place at the junction between Gln-Arg and Ser. Comparative analysis suggests that dengue NS3 and NS5 may be involved in enzymatic activities related to viral replication and/or transcription. Putative nonstructural proteins NS2a, NS2b, NS4a, and NS4b are extremely hydrophobic, suggesting that these proteins are most likely associated with cellular membranes.

Amino Acid Sequence↗
PubMed1990

Molecular evolution and distribution of dengue viruses type 1 and 2 in nature.

During the past several decades, dengue viruses have progressively extended their geographic distribution, and are currently some of the most important mosquito-borne viruses associated with human illness. Determining the genetic variability and transmission patterns of these RNA viruses is crucial in developing effective control strategies for the disease. Primer-extension sequencing of less than 3% of the dengue genome (across the E/NS1 gene junction) provided sufficient information for estimating genetic relationships among 40 dengue type 1 and 40 type 2 virus isolates from diverse geographic areas and hosts. A quantitative comparison of these 240-nucleotide-long sequences revealed previously unrecognized evolutionary relationships between disease outbreaks. Five distinct virus genotypic groups were detected for each of the two serotypes. The evolutionary rates of epidemic dengue viruses of types 1 and 2 were similar, although the transmission pathways of these viruses around the world are different. For dengue type 2, one genotypic group represents an isolated, forest virus cycle which seems to have evolved independently in West Africa. This is the first genetic evidence of the existence of a sylvatic cycle of dengue virus, which is clearly distinct from outbreak viruses.

Amino Acid Sequence↗
PubMed2005

Leptospirosis among patients presenting with dengue-like illness in Puerto Rico.

Leptospirosis is difficult to distinguish from dengue fever without laboratory confirmation. Sporadic cases/clusters of leptospirosis occur in Puerto Rico, but surveillance is passive and laboratory confirmation is rare. We tested for leptospirosis using an IgM ELISA on sera testing negative for dengue virus IgM antibody and conducted a case-control study assessing risk factors for leptospirosis, comparing clinical/laboratory findings between leptospirosis (case-patients) and dengue patients (controls). Among 730 dengue-negative sera, 36 (5%) were positive for leptospirosis. We performed post mortem testing for leptospirosis on 12 available specimens from suspected dengue-related fatalities; 10 (83%) tested positive. Among these 10 fatal cases, pulmonary hemorrhage and renal failure were the most common causes of death. We enrolled 42 case-patients and 84 controls. Jaundice, elevated BUN, hyperbilirubinemia, anemia, and leukocytosis were associated with leptospirosis (p < .01 for all). Male sex, walking in puddles, rural habitation, and owning horses were independently associated with leptospirosis. Epidemiological, clinical, and laboratory criteria may help distinguish leptospirosis from dengue and identify patients who would benefit from early antibiotic treatment.

Adolescent↗
PubMed2006

EEG in dengue virus infection with neurological manifestations: a clinical and CT/MRI correlation.

OBJECTIVE: To evaluate electroencephalography (EEG) changes in dengue virus infection and correlate these with clinical, laboratory and CT/MRI changes. METHODS: Consecutive patients with dengue virus infection were prospectively evaluated. A detailed history and clinical examination were carried out. Level of consciousness was assessed by Glasgow Coma scale (GCS). Cranial CT scan or MRI or both were carried out. EEG was carried out within 24h of hospitalization and repeated after 15-30 days. Outcome was defined at 1 month into death, poor, partial and complete recovery. RESULTS: Twenty-four patients aged 5-65 years with dengue virus infection having neurological manifestations were included; of whom six were females. EEG revealed theta to delta slowing in 11 out of 20 patients. Five of these patients had seizures, 12 altered sensorium, 3 hypotension, 9 CSF pleocytosis, 3 moderate to severe liver dysfunction and 2 MRI abnormalities who had Japanese encephalitis virus coinfection. Presence of EEG slowing correlated with altered sensorium and depth of coma but not with outcome. At 1 month, three patients died and 16 had complete, three partial and two poor recovery. CONCLUSIONS: EEG revealed non-specific slowing in 55% patients with dengue virus infection, which correlated with level of consciousness but not with CT/MRI abnormalities or clinical recovery. SIGNIFICANCE: Dengue virus infection results in non-specific EEG slowing in 55% patients, which may be due to dengue virus encephalitis per se or associated confounding variables such as seizure, metabolic encephalopathy, or structural brain lesion.

Adult↗
PubMed2005

Acute transverse myelitis following dengue virus infection.

The spinal cord is infrequently affected following dengue virus infection. We report a case of transverse myelitis that developed 2 weeks after acute dengue infection and review the literature to elucidate the pathogenesis of spinal cord involvement in dengue infection. We postulate that temporal factors may play a role in the different clinical manifestations, i.e. that acute parainfectious dengue infection presents with flaccid paralysis, whereas late-stage (postinfectious) dengue infection, presents with spastic weakness. Further studies need to be performed to elucidate the mechanisms of spinal neurological damage in dengue.

Adult↗
PubMed2006

What do community-based dengue control programmes achieve? A systematic review of published evaluations.

Owing to increased epidemic activity and difficulties in controlling the insect vector, dengue has become a major public health problem in many parts of the tropics. The objective of this review is to analyse evidence regarding the achievements of community-based dengue control programmes. Medline, EMBASE, WHOLIS and the Cochrane Database of Systematic Reviews were searched (all to March 2005) to identify potentially relevant articles using keywords such as 'Aedes', 'dengue', 'breeding habits', 'housing' and 'community intervention'. According to the evaluation criteria recommended by the Cochrane Effective Practice and Organisation of Care Review Group, only studies that met the inclusion criteria of randomised controlled trials (RCT), controlled clinical trials (CCT), controlled before and after trials (CBA) or interrupted time series (ITS) were included. Eleven of 1091 studies met the inclusion criteria. Of these, two were RCTs, six were CBAs and three were ITS. The selected studies varied widely with respect to target groups, intervention procedures and outcome measurements. Six studies combined community participation programmes with dengue control tools. Methodological weaknesses were found in all studies: only two papers reported confidence intervals (95% CI); five studies reported P-values; two studies recognised the importance of water container productivity as a measure for vector density; in no study was cluster randomisation attempted; and in no study were costs and sustainability assessed. Evidence that community-based dengue control programmes alone and in combination with other control activities can enhance the effectiveness of dengue control programmes is weak.

Community Health Services↗
PubMed2006

Induction of neutralizing antibodies and T cell responses by dengue virus type 2 envelope domain III encoded by plasmid and adenoviral vectors.

Dengue is a re-emerging public health problem in many developing nations. There is neither a specific antiviral therapy to treat nor a licensed vaccine to prevent dengue infections. In recent years, the carboxy-terminal region of the major dengue virion envelope (E) protein, known as domain III, has emerged as a significant sub-unit vaccine candidate. In this study, we created a recombinant adenovirus capable of expressing the E domain III (EDIII) of dengue virus type 2 (DEN-2) and tested it in combination with a plasmid encoding the same domain to determine its potential as a possible dengue vaccine candidate. We examined the relative efficacies of plasmid prime/Ad boost (P/A) and Ad prime/plasmid boost (A/P) regimens in eliciting DEN-2 virus-specific immune responses. Both regimens resulted in the induction of antibodies that specifically bound to and neutralized the infectivity of DEN-2 virus. Splenocytes from immunized mice, stimulated in vitro, manifested a significant proliferative response accompanied by the production of high levels of interferon-gamma, but moderately elevated levels of interleukin-4, indicative of a predominantly Th1 type response. Based on a comparison of the parameters investigated, the immune response induced by the A/P regimen appeared to be relatively more potent. Our data suggest that EDIII may be valuable in the efforts to develop plasmid- and Ad-vectored dengue vaccines.

Adenoviridae↗
PubMedDate not supplied

The risk of yellow fever in a dengue-infested area.

Yellow fever and dengue are viral infections that in urban centres are transmitted by the same arthropod vector, a mosquito of the genus Aedes. In order to estimate the risk of an epidemic of urban yellow fever in a dengue-infested area we calculated the threshold in the basic reproduction number, R0, of dengue, above which any single sylvatic yellow fever-infected individual will trigger an urban yellow fever epidemic. Specifically, we analysed the relationship between the extrinsic incubation period and the duration of viraemia, from which it is possible to define the R0 for dengue that would also suggest an outbreak potential for yellow fever. We also calculated the critical proportion of people to vaccinate against yellow fever in order to prevent an epidemic in a dengue-endemic area. The theory proposed is illustrated by the case of São Paulo State in southern Brazil, where dengue is endemic and the risk of urban yellow fever is already imminent.

Aedes↗
PubMedDate not supplied

Assessment of body fluid compartment volumes by multifrequency bioelectrical impedance spectroscopy in children with dengue.

Dengue haemorrhagic fever (DHF), the most severe form of illness following infection with a dengue virus, is characterized by plasma leakage and a period of increased microvascular permeability. Monitoring of plasma volume and body fluid compartment shifts is an integral part of the clinical management of DHF, and is crucial to the performance of clinical research studies on DHF pathogenesis. Multifrequency bioelectrical impedance spectroscopy (BIS) was assessed as a non-invasive method to monitor body fluid compartment shifts in children participating in a prospective, hospital-based, study of dengue virus infections in Thailand. Over the 48 h surrounding defervescence, the extracellular water/intracellular water ratio (ECW/ICW) rose in children with dengue virus infections and correlated with increasing disease severity [DHF > intermediate dengue fever (DF)/DHF > DF]. Plasma leakage remained within the ECW compartment and was not directly measured by multifrequency BIS. Expansion of the ECW space in DHF appeared to be primarily due to diminished renal water clearance. During the course of dengue illness, multifrequency BIS did not improve on serial haematocrit and bodyweight determinations for monitoring plasma volume contraction and ECW expansion, respectively.

Body Fluid Compartments↗
PubMedDate not supplied

Epidemic dengue 2 in the city of Djibouti 1991-1992.

From October 1991 to February 1992, an outbreak of acute fever (in which thick blood films were negative for malaria) spread rapidly in the city of Djibouti, Djibouti Republic, affecting all age groups and both nationals and foreigners. The estimated number of cases was 12,000. The clinical features were consistent with a non-haemorrhagic dengue-like illness. Serum samples from 91 patients were analysed serologically for flavivirus infection (dengue 1-4, West Nile, yellow fever, Zika, Banzi, and Uganda-S), and virus isolation was attempted. Twelve strains of dengue 2 virus were isolated. Dengue infection was confirmed by a 4-fold or greater rise in immunoglobulin (Ig) G antibody in paired serum specimens, the presence of IgM antibody, or isolation of the virus. Overall, 46 of the suspected cases (51%) were confirmed virologically or had serological evidence of a recent flavivirus infection. Statistical analysis showed that the presence of a rash was the best predictor of flavivirus seropositivity. In November 1992, Aedes aegypti was widespread and abundant in several districts of Djibouti city. A serological study of serum samples collected from Djiboutian military personnel 5 months before the epidemic showed that only 15/177 (8.5%) had flavivirus antibodies. These findings, together with a negative serosurvey for dengue serotypes 1-4 and yellow fever virus performed in 1987, support the conclusion that dengue 2 virus has only recently been introduced to Djibouti.

Adolescent↗