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

Dengue viruses occur as four antigenically related but distinct serotypes transmitted to humans by Aedes aegypti mosquitoes. These viruses generally cause a benign syndrome, dengue fever, in the American and African tropics, and a severe syndrome, dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS), in Southeast Asian children. This severe syndrome, which recently has also been identified in children infected with the virus in Puerto Rico, is characterized by increased vascular permeability and abnormal hemostasis. It occurs in infants less than 1 year of age born to dengue-immune mothers and in children 1 year and older who are immune to one serotype of dengue virus and are experiencing infection with a second serotype. Dengue viruses replicate in cells of mononuclear phagocyte lineage, and subneutralizing concentrations of dengue antibody enhance dengue virus infection in these cells. This antibody-dependent enhancement of infection regulates dengue disease in human beings, although disease severity may also be controlled genetically, possibly by permitting and restricting the growth of virus in monocytes. Monoclonal antibodies show heterogeneous distribution of antigenic epitopes on dengue viruses. These epitopes serve to regulate disease: when antibodies to shared antigens partially neutralize heterotypic virus, infection and disease are dampened; enhancing antibodies alone result in heightened disease response. Further knowledge of the structure of dengue genomes should permit rapid advances in understanding the pathogenetic mechanisms of dengue.

https://science.sciencemag.org/content/sci/239/4839/476.full.pdf

Pathogenesis of dengue: challenges to molecular biology

Foot-and-mouth disease (FMD) is a highly contagious disease of cloven-hoofed animals. The disease was initially described in the 16th century and was the first animal pathogen identified as a virus. Recent FMD outbreaks in developed countries and their significant economic impact have increased the concern of governments worldwide. This review describes the reemergence of FMD in developed countries that had been disease free for many years and the effect that this has had on disease control strategies. The etiologic agent, FMD virus (FMDV), a member of the Picornaviridae family, is examined in detail at the genetic, structural, and biochemical levels and in terms of its antigenic diversity. The virus replication cycle, including virus-receptor interactions as well as unique aspects of virus translation and shutoff of host macromolecular synthesis, is discussed. This information has been the basis for the development of improved protocols to rapidly identify disease outbreaks, to differentiate vaccinated from infected animals, and to begin to identify and test novel vaccine candidates. Furthermore, this knowledge, coupled with the ability to manipulate FMDV genomes at the molecular level, has provided the framework for examination of disease pathogenesis and the development of a more complete understanding of the virus and host factors involved.

Foot-and-Mouth Disease

The antigenicity and protective effect of live, oral adenovirus type 7 (ADV-7) vaccine given simultaneously with the live, oral adenovirus type 4 (ADV-4) vaccine was evaluated in trainees at Fort Dix, New Jersey, during an outbreak of acute respiratory disease (ARD) due to ADV-7. The study was done in one cohort of six companies; by random selection, 20% of the men received both ADV-7 and ADV-4 vaccines (test group), and 80% received a placebo and ADV-4 vaccine (control group). No untoward reactions were noted. Eighty-six percent of trainees in the test group who lacked neutralizing (N) antibody to both types of adenoviruses developed N antibody to ADV-7 after immunization. No decrease in the antigenicity of the ADV-4 vaccine was evident when it was given with the ADV-7 vaccine. The rate of hospitalization due to ARD (47%) and the rate of ARD associated with ADV-7 (96%) were lower in the test group. This study confirmed the safety and antigenicity of ADV-7 vaccine when administered with ADV-4 vaccine and showed that the administration of the vaccines together protected against ARD associated with ADV-7.

Immunization with Live Types 7 and 4 Adenovirus Vaccines. II. Antibody Response and Protective Effect against Acute Respiratory Disease Due to Adenovirus Type 7

18 – Chemical and Antigenic Structure of Flaviviruses

Trypsin treatment of adherent human monocytes greatly reduced or eliminated the ability of these cells to support dengue virus replication. However, addition of dilute (nonneutralizing) antibody to the inoculum and the culture medium resulted in viral yields similar to those from monocytes not treated with trypsin. These results suggested that viral entry was facilitated by phagocytosis of immune complexes via Fc receptors on the monocytes. This concept was tested by (i) pretreating monocytes with aggregated gamma globulin, which resulted in a 40-fold reduction of viral yields after infection with dilute antibody-virus complexes and (ii) forming an immune complex with virus, antivirus F(ab')2 fragments, and rabbit anti-human Fab. Whereas F(ab')2 fragments alone would not enhance virus replication in trypsin-treated monocytes, the immune complex containing a rabbit Fc piece did increase the yield of dengue virus. These results suggest that dengue virus can infect a cultured monocyte in two ways: (i) through a viral receptor that is trypsin sensitive or (ii) through an Fc receptor that is not trypsin sensitive.

Evidence for two mechanisms of dengue virus infection of adherent human monocytes: trypsin-sensitive virus receptors and trypsin-resistant immune complex receptors.

Dengue type 2 virus replication was detected in the U-937 human monocyte cell line when the virus inoculum and the culture medium contained flavivirus antibodies diluted beyond their neutralizing titers. This was in marked contrast to yellow fever virus, which replicated very well in the absence of antibodies; however, 10-fold-higher yields of yellow fever virus could be obtained in the presence of flavivirus antibodies. These infection-enhancing antibodies were obtained from either a dengue type 2 human antiserum or reference hyperimmune obtained from either a dengue type 2 human antiserum or reference hyperimmune mouse ascitic fluid. The infection enhancement phenomenon, previously shown to be due to infection of Fc receptor-bearing cells with virus-antibody complexes, was completely blocked by preincubation of the cells with aggregated gamma globulin. The blocking results suggested an Fc receptor-mediated infection of the U-937 cells as well. A panel of monoclonal antibodies, previously characterized as either virus type specific or flavivirus cross-reactive and with mouse immunoglobulin subclasses G1 and G2a in both categories, were tested for their infection enhancement characteristics. A type-specific neutralizing monoclonal antibody preparation that was diluted beyond its neutralization titer did not cause infection enhancement, nor did low-level neutralizing monoclonal antibodies that were dengue serotype specific by the hemagglutination inhibition test. Only flavivirus cross-reactive monoclonal antibodies caused infection enhancement, irrespective of whether the immunoglobulins were G1 or G2a. These cross-reactive flavivirus determinants may reside at the tips of the glycoprotein projections on the virus particles, enabling the Fc ends of the cross-reactive antibodies attached to these determinants to interact with Fc receptors on susceptible cells.

https://iai.asm.org/content/iai/36/3/1036.full.pdf

Infection enhancement of dengue type 2 virus in the U-937 human monocyte cell line by antibodies to flavivirus cross-reactive determinants.

Dengue virus, type 2, in viremic human sera and after passage in cell cultures produces mixtures of small and large plaques when assayed in LLC-MK2 cells. Clones of dengue virus type 2 obtained by plaque selection in primary green monkey kidney cell cultures were tested for temperature sensitivity in vitro and for virulence by intracerebral inoculation of suckling mice. Sublines of a small-plaque clone were found to have lower nonpermissive temperatures than the parent virus by both plaque formation and release of infectious virus into the culture media. Small-plaque sublines were significantly less virulent in suckling mice than was the parent virus. Sublines from a large-plaque clone were not temperature sensitive and closely resembled parent virus mixed-plaque morphology. When small-plaque sublines were serially passaged using undiluted inocula, reversion occurred as evidenced by the appearance of large plaques and return of mouse virulence. Small-plaque virus could be maintained through several serial passages without reversion by using low-input inocula. Desirable passage history as well as temperature-sensitive and attentuation characteristics of the S-1 small-plaque subline make it appear suitable as a vaccine candidate virus.

https://iai.asm.org/content/iai/14/5/1221.full.pdf

Philip K. Russell

Papers

Immunization with Live Types 7 and 4 Adenovirus Vaccines. II. Antibody Response and Protective Effect against Acute Respiratory Disease Due to Adenovirus Type 7

18 – Chemical and Antigenic Structure of Flaviviruses

Evidence for two mechanisms of dengue virus infection of adherent human monocytes: trypsin-sensitive virus receptors and trypsin-resistant immune complex receptors.

Infection enhancement of dengue type 2 virus in the U-937 human monocyte cell line by antibodies to flavivirus cross-reactive determinants.

Isolation of a temperature-sensitive dengue-2 virus under conditions suitable for vaccine development.