Evolution of Two Major Zika Virus Lineages: Implications for Pathology, Immune Response, and Vaccine Development

Abstract

Zika virus (ZIKV) became a public health emergency of global concern in 2015 due to its rapid expansion from French Polynesia to Brazil, spreading quickly throughout the Americas. Its unexpected correlation to neurological impairments and defects, now known as congenital Zika syndrome, brought on an urgency to characterize the pathology and develop safe, effective vaccines. ZIKV genetic analyses have identified two major lineages, Asian and African, which have undergone substantial changes during the past 50 years. Although ZIKV infections have been circulating throughout Africa and Asia for the later part of the 20th century, the symptoms were mild and not associated with serious pathology until now. ZIKV evolution also took the form of novel modes of transmission, including maternal-fetal transmission, sexual transmission, and transmission through the eye. The African and Asian lineages have demonstrated differential pathogenesis and molecular responses in vitro and in vivo. The limited number of human infections prior to the 21st century restricted ZIKV research to in vitro studies, but current animal studies utilize mice deficient in type I interferon (IFN) signaling in order to invoke enhanced viral pathogenesis. This review examines ZIKV strain differences from an evolutionary perspective, discussing how these differentially impact pathogenesis via host immune responses that modulate IFN signaling, and how these differential effects dictate the future of ZIKV vaccine candidates.

Keywords: Zika virus; evolution; immunology; phylogeny; tissue tropism; transmission; vaccines.

Figure 1

Phylogenetic analysis of Zika virus (ZIKV) genomes by host. (A) Phylogenetic analysis of 296 available ZIKV genomes was organized according to the host species of isolation using Virus Variation analysis system available through NCBI. Only complete nucleotide genomes were screened and duplicate strains were removed to produce 296 unique strains. Strains isolated from humans, mosquitos, NHPs, and cell cultures are labeled with red (humans), blue (mosquitos), green (NHP), and aqua (cell cultures). (B) The total number of strains isolated per host species was used to derive the percentage of each host within the grand total.

Figure 2

Phylogenetic analysis of Zika virus (ZIKV) genomes by region. (A) Phylogenetic analysis of available ZIKV genomes was organized according to lineage, followed by continent of isolation using Virus Variation analysis system available through NCBI. Only complete nucleotide genomes were screened and duplicate strains were removed to produce 296 unique strains. Strains were clustered from Africa (red), from the Americas (Asian lineage) (blue); and from Asia and Oceania (Asian lineage) (green). (B) The total number of strains isolated per continent was used to derive the percentage of each host within the grand total.

Figure 3

Zika virus activates signaling pathways that promote transcription of interferon (IFN) genes differentially. (A) The NS5 protein from African lineage binds and prevents NF-kB function. Asian lineage non-structural proteins NS5, NS4, and NS1 act to inhibit IRF3 and IRF7 functionality, thus inhibiting IFN production. (B) IFN Type I phosphorylates STAT1 and STAT2 and NS5 targets STAT2 for degradation. (C) Activation of Type II IFN signaling upon receptor binding phosphorylates STAT1 heterodimers and thus increases chemoattractant IFN-stimulated genes. (D) STAT2 is targeted for proteasomal degradation by NS5 resulting in an increased rate of STAT homodimerization and upregulation of anti-inflammatory cytokines.