Zika virus: An emergent neuropathological agent

Abstract

The emergence of Zika virus in the Americas has followed a pattern that is familiar from earlier epidemics of other viruses, where a new disease is introduced into a human population and then spreads rapidly with important public health consequences. In the case of Zika virus, an accumulating body of recent evidence implicates the virus in the etiology of serious pathologies of the human nervous system, that is, the occurrence of microcephaly in neonates and Guillain-Barré syndrome in adults. Zika virus is an arbovirus (arthropod-borne virus) and a member of the family Flaviviridae, genus Flavivirus. Zika virions are enveloped and icosahedral, and contain a nonsegmented, single-stranded, positive-sense RNA genome, which encodes 3 structural and 7 nonstructural proteins that are expressed as a single polyprotein that undergoes cleavage. Zika genomic RNA replicates in the cytoplasm of infected host cells. Zika virus was first detected in 1947 in the blood of a febrile monkey in Uganda's Zika Forest and in crushed suspensions of the Aedes mosquito, which is one of the vectors for Zika virus. The virus remained obscure, with a few human cases confined to Africa and Asia. There are two lineages of the Zika virus, African and Asian, with the Asian strain causing outbreaks in Micronesia in 2007 and French Polynesia in 2013-2014. From here, the virus spread to Brazil with the first report of autochthonous Zika transmission in the Americas in March 2015. The rapid advance of the virus in the Americas and its likely association with microcephaly and Guillain-Barré syndrome make Zika an urgent public health concern. Ann Neurol 2016;80:479-489.

FIGURE 1

Spread of Zika virus around the world. The spread of Zika virus around different parts of the world is shown. Countries are grouped by geographical location, and a date of the first reported Zika infection is given. The first group is in Africa, where the virus originated, with infections with dates for each country ranging from 1947 to 1981. Next, the virus spread to the Far East, with dates between 1966 and 2012, and thence to the Pacific Islands starting with an outbreak on Yap Island in 2007. More recently, Zika has spread to Central and South America between 2014 and 2016. Miscellaneous cases are grouped in North America first reported in 2007 and European countries first reported in 1972: these may be spread by air travel, laboratory infections, and other events. [Color figure can be viewed in the online issue, which is available at www.annalsofneurology.org.]

FIGURE 2

Transmission of Zika virus. Zika virus was originally transmitted in a sylvatic cycle between monkeys and Aedes mosquitoes in Africa. Zika was then spread by reciprocal infection of man and mosquitoes as shown, which is the major mode of transmission today. Zika virus can also be spread by sexual transmission from men to women via semen and can also be spread by blood transfusions. GBS 5 Guillain–Barré syndrome. [Color figure can be viewed in the online issue, which is available at www.annalsofneurology.org.]

FIGURE 3

Life cycle of Zika virus. Zika virus has a single-stranded positive RNA genome, which is about 11kb in length and is complexed with the viral capsid protein (C) within the nucleocapsid, whereas the outer membrane of the virion is a lipid bilayer containing the viral membrane protein (M), and envelope protein (E), as shown on the left. Virions attach to the surface of a host cell by interactions between viral surface glycoproteins and cell surface receptors and subsequently enter the cell by receptor-mediated endocytosis and are internalized into clathrin-coated pits (1). Acidification of the endosomal vesicle triggers conformational changes in the virion, fusion of the viral and cell membranes, and particle disassembly and the genome is released into the cytoplasm (2). The positive-sense genomic RNA is translated into a single polyprotein (3) that is processed cotranslationally and post-translationally by cellular and viral proteases (4). This cleavage makes a total of 10 proteins: 3 structural proteins (C, prM [glycosylated precursor to M], and E) and 7 nonstructural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5). The structural proteins are located at the N-terminus of the polyprotein, and the nonstructural proteins are found at the C-terminus (shown inset). Genome replication occurs on intracellular membranes known as vesicle packages, which facilitate the assembly of the viral replication complex containing viral RNA and cellular and viral proteins, for example, NS3 and NS5 (5). Replication initiates with negative-strand RNA synthesis, and this then serves as a template for the synthesis of multiple copies of the positive-strand genomic RNA (6). Virus assembly occurs on the surface of the endoplasmic reticulum (7) by budding, and nascent virus particles travel along the host secretory pathway through the trans-Golgi network (8), where virion maturation occurs followed by release from the cell by exocytosis (9). [Color figure can be viewed in the online issue, which is available at www.annalsofneurology.org.]