Abstract
Zika virus (ZIKV) is an emerging flavivirus responsible for a major epidemic in the Americas beginning in 2015. ZIKV associated with maternal infection can lead to neurological disorders in newborns, including microcephaly. Although there is an abundance of research examining the neurotropism of ZIKV, we still do not completely understand the mechanism by which ZIKV targets neural cells or how to limit neural cell infection. Recent research suggests that flaviviruses, including ZIKV, may hijack the cellular autophagy pathway to benefit their replication. Therefore, we hypothesized that ZIKV replication would be impacted when infected cells were treated with compounds that target the autophagy pathway. We screened a library of 94 compounds known to affect autophagy in both mammalian and insect cell lines. A subset of compounds that inhibited ZIKV replication without affecting cellular viability were tested for their ability to limit ZIKV replication in human neurons. From this second screen, we identified one compound, 7-ketocholesterol (7-KC), which inhibited ZIKV replication in neurons without significantly affecting neuron viability. Interestingly, 7-KC induces autophagy, which would be hypothesized to increase ZIKV replication, yet it decreased virus production. Time-of-addition experiments suggest 7-KC inhibits ZIKV replication late in the replication cycle. While 7-KC did not inhibit RNA replication, it decreased the number of particles in the supernatant and the relative infectivity of the released particles, suggesting it interferes with particle budding, release from the host cell, and particle integrity.
Highlights
Zika virus (ZIKV) is an emerging arbovirus that gained public attention in 2015 when maternal infection in the Americas was causally associated with congenital birth defects, including microcephaly [1]
To reduce ZIKV titer in mid-logarithmic growth phase (40 h post infection) [22], without negatively impacting viability compared to controls in Vero cells
These compounds produced a wide range of effects on ZIKV titer, though only approximately 30% were able to decrease ZIKV titer by at least one log compared to control (Figure 1A)
Summary
Zika virus (ZIKV) is an emerging arbovirus that gained public attention in 2015 when maternal infection in the Americas was causally associated with congenital birth defects, including microcephaly [1]. ZIKV belongs to the Flaviviridae family and is related to other important human pathogens, including dengue (DENV), yellow fever (YFV) and West Nile (WNV). ZIKV is an enveloped virus with a positive-sense RNA genome that translates into a single polypeptide, which is later cleaved into three structural and seven nonstructural viral proteins. Low pH in the endosome triggers viral-cellular membrane fusion, releasing the viral RNA genome into the host cell cytoplasm [2]. Transcription occurs in the cytoplasm and translation of ZIKV proteins occurs on membrane scaffolds near the endoplasmic reticulum (ER) [3]
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