key: cord-0945036-k8ochgrw
authors: Marques, Ernesto T. A.; Drexler, Jan Felix
title: Complex Scenario of Homotypic and Heterotypic Zika Virus Immune Enhancement
date: 2019-09-03
journal: mBio
DOI: 10.1128/mbio.01849-19
sha: 27f30484b7d87c1f6fbff4b299ba94ac09da9a3b
doc_id: 945036
cord_uid: k8ochgrw

nan

W e read the article by Shim and colleagues describing homotypic antibodydependent-enhancement (ADE) of Zika virus (ZIKV) infections by low-level ZIKVspecific antibodies (1) with great interest. ADE predominantly describes a mechanism by which infectious antibody-virus immune complexes efficiently bind to Fc gamma receptors of immune cells, facilitating the infection of otherwise poorly susceptible cells. As noted by Shim et al., ADE has been described for genetically diverse viruses, including feline coronaviruses, human immunodeficiency virus type 1, and cytomegalovirus (2, 3). Although likely not solely responsible, ADE is a major component of the development of severe secondary dengue virus (DENV) infections (4). While a potential homotypic ZIKV-mediated ADE of subsequent ZIKV infections is of significant interest, several questions remain. The affinity, avidity, capacity of the antibody to bind to complement factor, and role of distinct epitopes in cell entry are all critical aspects determining whether viral immune complexes will be neutralized and destroyed or whether they will facilitate infection. In essence, even a potent neutralizing antibody can form enhancing immune complexes when it is present in low concentrations, as shown for DENV (4) and more recently for the genetically divergent arbovirus Chikungunya virus (5) . Strikingly, we and others have recently shown that despite strong evidence for heterotypic ADE of ZIKV infection by DENV-specific antibodies in vitro and in murine infection models, prior DENV infection seems in fact to protect from both symptomatic Zika virus infection and congenital Zika syndrome (CZS) development in vivo (6) (7) (8) . Whether the findings from Shim et al., whose data were raised in vitro and in experimental infections of immunodeficient mice, are clinically relevant thus remains unknown. Notably, our groups previously found that mothers of CZS cases had significantly higher, not lower, ZIKV-specific antibody titers than controls (9, 10). One the one hand, these data seem at odds with the experimental data reported by Shim et al. On the other hand, antibody titrations were performed months after ZIKV infection, and maternal antibody titers in CZS cases may have been boosted by prolonged Zika viremia potentially elicited by fetal-maternal ZIKV shedding (11) . In any case, ZIKV spread rapidly throughout Latin America, infecting about 60% of the population in different regions (12, 13) . A hypothetical homotypic ZIKV ADE is thus highly unlikely to have affected CZS development during the 2015-2016 Zika outbreak. The findings from Shim et al. may become relevant in the long-and medium-term perspectives on the fate of Zika in the Americas, when ZIKV-specific antibody titers drop to levels that may mediate enhancement. Immediate experimental assessments will have to consider the duration and strength of both humoral and cellular ZIKV-and

Zika virus-immune plasmas from symptomatic and asymptomatic individuals enhance Zika pathogenesis in adult and pregnant mice

Maternal antibodies enhance or prevent cytomegalovirus infection in the placenta by neonatal Fc receptor-mediated transcytosis

Vaccine-induced enhancement of viral infections

Antibody-dependent enhancement of severe dengue disease in humans

Antibody-mediated enhancement aggravates chikungunya virus infection and disease severity

Impact of preexisting dengue immunity on Zika virus emergence in a dengue endemic region

Crossprotection of dengue virus infection against congenital Zika Syndrome, northeastern Brazil

Prior dengue virus infection and risk of Zika: a pediatric cohort in Nicaragua

Perinatal analyses of Zika-and dengue virusspecific neutralizing antibodies: a microcephaly case-control study in an area of high dengue endemicity in Brazil

Evidence for congenital Zika virus infection from neutralizing antibody titers in maternal sera, northeastern Brazil

Zika virus infection with prolonged maternal viremia and fetal brain abnormalities

High Zika virus seroprevalence in Salvador, northeastern Brazil limits the potential for further outbreaks

Seroprevalence, risk factor, and spatial analyses of Zika virus infection after the 2016 epidemic in Managua