Dengue viruses and mononuclear phagocytes. I. Infection enhancement by non-neutralizing antibody

Abstract

Cultured mononuclear peripheral blood leukocytes (PBL) from nonimmune human beings and monkeys are nonpermissive to dengue 2 virus (D2V) infection at multiplicities of infection of 0.001-0.1, but become permissive when non-neutralizing dengue antibody is added to medium. D2V infection occurred in PBL prepared from anti-coagulated but not from defibrinated plasma. Infection enhancement was produced by multiple lots of heterotypic anti-dengue raised in several mammalian species. Homotypic anti-dengue neutralized D2V at high concentrations but enhanced at low concentrations; enhancement end point in one serum was 1:320,000. The infection-enhancing factor was a noncytophilic antibody of the IgG class. D2V infection occurred in the absence of heat-labile complement components but did not occur when complexes were prepared with anti- dengue F(ab)(2). Treatment of PBL with several proteases increased permissiveness to D2V infection by immune complexes but not by virus alone. Two rhesus monkey serums collected 14 days after D2V infection contained an IgG antibody with high-titered enhancing activity but with no hemagglutination-inhibition or neutralizing activity. Virus-antibody complexes are irreversibly attached to PBL within 15 min and completely internalized in 60 min. There was considerable variation in cellular infection in different experiments, however, maximum virus yields usually exceeded 1,000 plaque-forming units per 1 x 10(6) PBL occurring between 2 and 4 days in culture. In vitro antibody-dependent infection of PBL provides a possible model for study of pathogenetic mechanisms in infants with dengue shock syndrome who passively acquire maternal anti-dengue IgG.

The pathogenesis of dengue

“…27, 43 The concept of ADE was initially proposed for dengue in 1977 and was supported by epidemiological observations in Cuba. 44,45 Data from Cuba demonstrated that DHF was more frequently observed in those patients who had evidence of previous infection with a different serotype. Recent work has provided further support for the concept of ADE.…”

Immunological enhancement and the pathogenesis of dengue haemorrhagic fever

“…When non-permissive human or monkey peripheral blood mononuclear cells are exposed to dengue virus in the presence of passively added anti-dengue antibody, viral replication takes place, provided that the antibody concentration is below the level that would neutralize the virus (Halstead & O'Rourke, 1977). These experiments provide the base upon which all subsequent dengue virus enhancement studies have been founded.…”

“…Using dengue virus type 2, Halstead & O'Rourke (1977) demonstrated a dependence upon cellular Fc receptors, those on the human mononuclear cells they were using being trypsin resistant. They also showed that enhancement was mediated by antibodies of the IgG class, that IgM and F (ab')2 fragments were not able to enhance (although IgM showed weak activity in the presence of complement, Halstead, 1980b), and that the mammalian species in Which the antibodies were raised was immaterial (Halstead & O'Rourke, 1977). The trypsin sensitivity of the dengue virus receptors on human mononuclear cells has been further studied by Daughaday et al (1981).…”

“…Using dengue virus type 2 as the test virus, Halstead & O'Rourke (1977) showed that antisera against heterotypic types 1, 3 & 4 dengue viruses would all enhance, as would homotypic antibody when diluted beyond the neutralising endpoint. In a separate study, again with dengue virus type 2, and using human mononuclear cells, Halstead, Porterfield & O'Rourke (1980) showed that a wide range of antisera prepared in rabbits against different flaviviruses were capable of mediating enhancement; antisera prepared in rabbits against alphaviruses, Bunyaviridae, or against normal mouse brain had no enhancing activity.…”

Dengue: a continuing global threat

“…The positive singlestrand RNA genome (FIG. 3), which is approximately 11 kb in length, has a single open reading frame that encodes three structural proteins -the capsid (C), membrane (M) and envelope (E) glycoproteins -and seven non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B and NS5 [18][19][20] . ADE occurs when mononuclear phagocytes are infected through their Fc receptors by immune complexes that form between DENVs and non-neutralizing antibodies.…”