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. 2018 Apr 23;9:597.
doi: 10.3389/fimmu.2018.00597. eCollection 2018.

Modulation of Dengue/Zika Virus Pathogenicity by Antibody-Dependent Enhancement and Strategies to Protect Against Enhancement in Zika Virus Infection

Free PMC article

Modulation of Dengue/Zika Virus Pathogenicity by Antibody-Dependent Enhancement and Strategies to Protect Against Enhancement in Zika Virus Infection

Rekha Khandia et al. Front Immunol. .
Free PMC article


Antibody-dependent enhancement (ADE) is a phenomenon in which preexisting poorly neutralizing antibodies leads to enhanced infection. It is a serious concern with mosquito-borne flaviviruses such as Dengue virus (DENV) and Zika virus (ZIKV). In vitro experimental evidences have indicated the preventive, as well as a pathogenicity-enhancing role, of preexisting DENV antibodies in ZIKV infections. ADE has been confirmed in DENV but not ZIKV infections. Principally, the Fc region of the anti-DENV antibody binds with the fragment crystallizable gamma receptor (FcγR), and subsequent C1q interactions and immune effector functions are responsible for the ADE. In contrast to normal DENV infections, with ADE in DENV infections, inhibition of STAT1 phosphorylation and a reduction in IRF-1 gene expression, NOS2 levels, and RIG-1 and MDA-5 expression levels occurs. FcγRIIA is the most permissive FcγR for DENV-ADE, and under hypoxic conditions, hypoxia-inducible factor-1 alpha transcriptionally enhances expression levels of FcγRIIA, which further enhances ADE. To produce therapeutic antibodies with broad reactivity to different DENV serotypes, as well as to ZIKV, bispecific antibodies, Fc region mutants, modified Fc regions, and anti-idiotypic antibodies may be engineered. An in-depth understanding of the immunological and molecular mechanisms of DENV-ADE of ZIKV pathogenicity will be useful for the design of common and safe therapeutics and prophylactics against both viral pathogens. The present review discusses the role of DENV antibodies in modulating DENV/ZIKV pathogenicity/infection and strategies to counter ADE to protect against Zika infection.

Keywords: Dengue virus; Zika virus; antibody-dependent enhancement; counteracting strategies; engineered antibodies; pathogenesis.


Figure 1
Figure 1
Events of immune response during Dengue virus (DENV) infection and DENV-antibody-dependent enhancement (ADE) infection. (A) DENV infection: (a) upon viral entry, pattern recognizing receptor (PRR) signaling activates RIG-1 and MDA-5, (b) IFN-α/β are produced, (c) NO production is upregulated, (d) phosphorylation of STAT1 is reduced, and (e) less viral progeny is produced. (B) DENV-ADE infection: (1) virus-antibody immune complex binds to FcγR and is trafficked inside the cell; (2) PRR signaling is not involved and RIG-1 and MDA-5 are suppressed; (3) IFN-α/β production is inhibited, (4) negative regulation of DAK and Atg5–Atg12; (5) disrupts the RIG-I/MDA-5 (PRRs) signaling cascade; (6) enhanced expression of p65 of NF-κB and degradation of I κB resulted in elevated levels of IL-6, IL-8, IL-1β, and TNF-α (pro-inflammatory cytokines); (7) IL-10 secretion enhances SOCS-3 and SOCS-1; (8) in turn attenuates STAT1 phosphorylation; (9) downregulation of IL-12 and IFN-γ; (10) NO production is suppressed; (11) autophagy is increased; and (12) more viral progeny is produced.
Figure 2
Figure 2
Strategies to counter Dengue virus (DENV)-antibody-dependent enhancement (ADE)/Zika virus (ZIKV). (1) Mutations in the Fc region: removal of native Fc N-linked glycosylation site and the “LALA” double mutation (Leu234Ala together with Leu235Ala) in the Fc region of antibody prevents binding to FcγR. (2) Bispecific antibodies: bispecific antibody (DVD-1A1D-2A10) with anti-DENV monoclonal antibody (mAb) 1A1D-2 (1A1D) specific to the E-DIII, check the virus attachment to the cell, and mAb 2A10, will bind to the E-DII and further prevents the endosomal fusion of the virus. This neutralizing antibody neutralizes all the DENV serotypes without inducing ADE. Similar strategies can be employed for the ZIKV. (3) Swapping of Fc region: the Fc region of D23-1G7C2-IgG1 can be changed to generate antibodies with each of IgG subclasses (IgG2–4). The swapping of the Fc region might result in reduced ADE activity in FcγRI and FcγRII-bearing THP-1 cells in the case of IgG2 or IgG4 subclasses. (4) Anti-idiotypic antibodies: anti-idiotypic antibodies (prM-AIDs) targeted to prM mAb largely reduces the symptoms of ADE.

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