Specificity, cross-reactivity, and function of antibodies elicited by Zika virus infection

Abstract

Zika virus (ZIKV), a mosquito-borne flavivirus with homology to Dengue virus (DENV), has become a public health emergency. By characterizing memory lymphocytes from ZIKV-infected patients, we dissected ZIKV-specific and DENV-cross-reactive immune responses. Antibodies to nonstructural protein 1 (NS1) were largely ZIKV-specific and were used to develop a serological diagnostic tool. In contrast, antibodies against E protein domain I/II (EDI/II) were cross-reactive and, although poorly neutralizing, potently enhanced ZIKV and DENV infection in vitro and lethally enhanced DENVdisease in mice. Memory Tcells against NS1 or E proteins were poorly cross-reactive, even in donors preexposed to DENV. The most potent neutralizing antibodies were ZIKV-specific and targeted EDIII or quaternary epitopes on infectious virus. An EDIII-specific antibody protected mice from lethal ZIKV infection, illustrating the potential for antibody-based therapy.A fter its introduction into Brazil in 2015, Zika virus (ZIKV) has spread rapidly, and in February 2016, the World Health Organization (WHO) declared it a Public Health Emergency of International Concern (1-3). The main route of ZIKV infection is through bites by Aedes mosquitos, but the virus may also be sexually (4) and vertically transmitted (5). Although most of the ZIKV infections are asymptomatic or cause only mild symptoms, there is evidence that ZIKV infection can lead to neurological complications, such as Guillain-Barré syndrome in adults (6) and congenital birth defects, including microcephaly in the developing fetus (5,7,8), likely through its ability to infect human neural progenitor cells (9).Whereas flavivirus envelope (E) proteins mediate fusion and are the main target of neutralizing antibodies, the nonstructural protein 1 (NS1) is secreted by infected cells and is involved in immune evasion and pathogenesis (10). Two recent studies showed a high level of structural similarity between the E protein of ZIKV and that of other flaviviruses-such as dengue virus (DENV), yellow fever virus (YFV), and West Nile virus (WNV)-but also revealed distinct features that may be related to the ZIKV neurotropism (11,12). Similarly, the structural analysis of ZIKV NS1 revealed conserved features with NS1 of other flaviviruses, although with different electrostatic characteristics (13).A phenomenon that is characteristic of certain flaviviruses is the disease-enhancing activity of cross-reactive antibodies elicited by previous infections by heterologous viruses, termed antibodydependent enhancement (ADE). In the case of DENV, for which four serotypes are known, there is epidemiological evidence that a primary infection protects from reinfection with the same serotype but represents a risk factor for the development of severe disease upon reinfection with a different serotype (14). The exacerbated disease is triggered by E-and prM-specific antibodies that fail to neutralize the incoming virus but instead enhance its capture by Fc receptor-expressing (FcR + ) cells, leading to enhanced vi...

Zika virus infection followed by a first episode of psychosis: another flavivirus leading to pure psychiatric symptomatology

“…RT-PCRs for ZIKV resulted positive in multiple blood samples. An intense cross-reaction was observed across DENV and ZIKV ELISA titers, 3,4 leading us to conclude that this was the case. After five days of Haloperidol with no response, the prescription was changed to Risperidone 2 mg/day and remission was achieved in three days.…”

“…Of the eight included trials, only three provided some information about missing sessions ( Table 1). The two first trials 4,5 mentioned the maximum number of sessions that could be missed (no more than two non-consecutive sessions) before excluding the subject and how they handled such cases. Zanã o et al stated that missing two sessions in the acute treatment phase might not change the final result,…”

Exclusive and Common Subsets of Zika Virus Polyprotein Mutants

“…The prM and E proteins initially exist as precursors within the structural domain of the polyprotein. Antibody and T-cell responses against the NS1, NS2, NS3, NS4B and NS5 non-structural polyproteins have been reported [10,11,13,14].…”

“…There are other, specific immunological human host factors that affect the Zika virus. Neutralizing antibodies against the prM precursor membrane protein (prM) and envelope E protein have been reported [10][11][12]. The prM and E proteins initially exist as precursors within the structural domain of the polyprotein.…”

Características de la estructura molecular de las proteínas E del virus Zika y E1 del virus de la rubeola. Posibles implicaciones en el neurotropismo y en las alteraciones del sistema nervioso

“…Asimismo, la comprobación serológica de la infección por el ZIKV en pacientes con el síndrome de Guillain-Barré y los estudios de conducción nerviosa sugieren la presencia de una neuropatía axonal aguda (4,8,9). Aunque la detección del virus o su confirmación virológica se logra en menos del 50 % de los pacientes afectados por el síndrome (10), el hallazgo de anticuerpos IgG anti-glucolípidos, especialmente los dirigidos a gangliósidos, así como los datos epidemiológicos, clínicos y experimentales, también sugieren un neurotropismo y una neurotoxicidad viral directa del ZIKV en el sistema nervioso periférico (4,6,10); sin embargo, aún se desconocen los mecanismos celulares y moleculares del neurotropismo y la patogenia del virus, y de las alteraciones del sistema nervioso, incluidos la microcefalia y el síndrome de Guillain-Barré.…”