**1. Introduction**

Zika virus (ZIKV) is a neurotropic arthropod-borne virus belonging to Flaviviridae family, along with other Flaviviruses capable of infecting central nervous system, such as West Nile Virus, St. Louis Encephalitis Virus, and Japanese Encephalitis Virus. It is commonly transmitted though the bite of an infected *Aedes aegypti* mosquito. Importantly, besides the mosquito bites, human-to-human modes of transmission have also been documented, including sexual activity, blood transfusions, and mother to fetus [1].

Since its first confirmed human infection in the 1960s, there were three documented Zika virus (ZIKV) outbreaks worldwide. The first two occurred in Micronesia and French Polynesia in 2007 and 2013, respectively. The most recent one (2015–2016) started in the northeastern region of Brazil and rapidly spread through South America, the Caribbean, and Mexico. By July 2016, locally transmitted cases of Zika infection were first reported in the United States (Florida). According to the World Health Organization (WHO), 73 di fferent countries had reported ZIKV infections by February of 2016 [2,3]. According to the Centers for Disease Control & Prevention, there have been no recorded local transmissions of the Zika virus in the continental United States in 2018 and 2019. However, with the globally increasing rate of travelling and the historical ability of viruses to acquire genetically modified virulence, the search for e ffective methods of Zika prevention and control remains important.

ZIKV infections in adults have been associated with neurological conditions such as Guillain-Barré syndrome, acute flaccid paralysis, and meningoencephalitis [4–7]. The Brazilian outbreak was the first time that ZIKV infection (presented in pregnan<sup>t</sup> women) was correlated to congenital microcephaly in newborns [8,9]. Both in vitro and in vivo models have demonstrated that ZIKV has a tropism toward human neural progenitor cells [10–12]. In these cells, ZIKV infection is followed by apoptosis, corroborating the hypothesis of ZIKV as the etiological agen<sup>t</sup> of these neurological disorders [4,5,10–12]. Further, independent studies have shown that the microcephaly and neural development-associated phenotypes is not a distinct feature of the Asian lineage [12–16]. However, the precise molecular mechanism(s) underlying these ZIKV-related manifestations is not understood.

ZIKV is a Baltimore class IV arbovirus from the Flaviviridae family. The ZIKV genome encodes a polyprotein that is processed by both viral and host proteases into ten proteins. Three of them (the capsid, pre-membrane, and envelope) are responsible for the structural organization of the virus. The other seven are non-structural (NS) proteins (NS1, NS2A NS2B, NS3, NS4A, NS4B, and NS5) responsible for regulatory function, viral replication, and subvert host responses [17].

The identification of virus–host protein–protein interaction is essential to better understand viral pathogenesis and to identify cellular mechanisms that could be pharmacologically targeted [18]. To gain further insight into the ZIKV pathogenesis, we generated a virus–host protein–protein interaction network focused on the interactions mediated by the non-structural proteins encoded by the Brazilian ZIKV genotype. Here, we present a network composed of proteins related to neuron projection development, microcephaly-associated disorders, and by protein complexes linked to replication and infection of other members of the Flaviviridae family. In addition, we integrate our dataset with previously published ZIKV protein interaction networks, highlighting common and unique protein interaction partners [19–21]. In addition, we show a PIAS1-dependent control of NS5 protein stability. Taken together, these data can be used as a resource to improve the understanding of the ZIKV pathogenesis and identify putative pharmacological targets for future treatment approaches.
