Complete Genome Sequences of Five Zika Virus Isolates

Ladner, Jason T.; Wiley, Michael R.; Prieto, Karla; Yasuda, Chadwick Y.; Nagle, Elyse R.; Kasper, Matthew R.; Reyes, Daniel; Vasilakis, Nikolaos; Heang, Vireak; Weaver, Scott C.; Haddow, Andrew D.; Tesh, Robert B.; Sovann, Ly; Palacios, Gustavo

doi:10.1128/genomea.00377-16

Cited by 45 publications

(41 citation statements)

References 13 publications

(17 reference statements)

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“…It should be noted, however, that at 10 µM concentrations, ivermectin, mefloquine, and to a lesser extent cyclosporine A, altered cellular light scattering features, which suggests cell toxicity, and reduced the number of cells that could be confidently analyzed by flow cytometry (Figure 4C and D, and Figure S4). We additionally tested a ZIKV strain from the African lineage (ZIKV DAK_41525)(Ladner et al, 2016) on hNSCs with a drug panel including sertraline and bortezomib. At 1 µM concentrations MPA, ivermectin and bortezomib all exerted antiviral effects and only the latter exhibited moderate toxicity (Figure 4 E and F).…”

Section: Resultsmentioning

confidence: 99%

A Screen of FDA-Approved Drugs for Inhibitors of Zika Virus Infection

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Powell

et al. 2016

Cell Host & Microbe

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Summary Currently there are no approved vaccines or specific therapies to prevent or treat Zika virus (ZIKV) infection. We interrogated a library of FDA-approved drugs for their ability to block infection of human HuH-7 cells by a newly isolated ZIKV strain (ZIKV MEX_I_7). More than 20 out of 774 tested compounds decreased ZIKV infection in our in vitro screening assay. Selected compounds were further validated for inhibition of ZIKV infection in human cervical, placental and neural stem cell lines, as well as primary human amnion cells. Established anti-flaviviral drugs (e.g., bortezomib and mycophenolic acid) and others that had no previously known anti-viral activity (e.g., daptomycin) were identified as inhibitors of ZIKV infection. Several drugs reduced ZIKV infection across multiple cell types. This study identifies drugs that could be tested in clinical studies of ZIKV infection and provides a resource of small molecules to study ZIKV pathogenesis.

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Section: Resultsmentioning

confidence: 99%

A Screen of FDA-Approved Drugs for Inhibitors of Zika Virus Infection

Barrows

Campos

Powell

et al. 2016

Cell Host & Microbe

459

403

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“…Given the urgent need to increase our understanding of ZIKV, we asked whether RPLP1/2 are also required for ZIKV infection. We analyzed ZIKV isolates of the American lineage (isolate MEX_I_7) (33) and African lineage (isolate 41525) (34). To this end, we knocked down RPLP1/2 in A549 and HuH-7 cells and then infected the cells at an MOI of 1.…”

Section: Resultsmentioning

confidence: 99%

RPLP1 and RPLP2 Are Essential Flavivirus Host Factors That Promote Early Viral Protein Accumulation

Campos

Wong

Xie

et al. 2017

J Virol

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The Flavivirus genus contains several arthropod-borne viruses that pose global health threats, including dengue viruses (DENV), yellow fever virus (YFV), and Zika virus (ZIKV). In order to understand how these viruses replicate in human cells, we previously conducted genome-scale RNA interference screens to identify candidate host factors. In these screens, we identified ribosomal proteins RPLP1 and RPLP2 (RPLP1/2) to be among the most crucial putative host factors required for DENV and YFV infection. RPLP1/2 are phosphoproteins that bind the ribosome through interaction with another ribosomal protein, RPLP0, to form a structure termed the ribosomal stalk. RPLP1/2 were validated as essential host factors for DENV, YFV, and ZIKV infection in two human cell lines: A549 lung adenocarcinoma and HuH-7 hepatoma cells, and for productive DENV infection of Aedes aegypti mosquitoes. Depletion of RPLP1/2 caused moderate cell-line-specific effects on global protein synthesis, as determined by metabolic labeling. In A549 cells, global translation was increased, while in HuH-7 cells it was reduced, albeit both of these effects were modest. In contrast, RPLP1/2 knockdown strongly reduced early DENV protein accumulation, suggesting a requirement for RPLP1/2 in viral translation. Furthermore, knockdown of RPLP1/2 reduced levels of DENV structural proteins expressed from an exogenous transgene. We postulate that these ribosomal proteins are required for efficient translation elongation through the viral open reading frame. In summary, this work identifies RPLP1/2 as critical flaviviral host factors required for translation.IMPORTANCE Flaviviruses cause important diseases in humans. Examples of mosquito-transmitted flaviviruses include dengue, yellow fever and Zika viruses. Viruses require a plethora of cellular factors to infect cells, and the ribosome plays an essential role in all viral infections. The ribosome is a complex macromolecular machine composed of RNA and proteins and it is responsible for protein synthesis. We identified two specific ribosomal proteins that are strictly required for flavivirus infection of human cells and mosquitoes: RPLP1 and RPLP2 (RPLP1/2). These proteins are part of a structure known as the ribosomal stalk and help orchestrate the elongation phase of translation. We show that flaviviruses are particularly dependent on the function of RPLP1/2. Our findings suggest that ribosome composition is an important factor for virus translation and may represent a regulatory layer for translation of specific cellular mRNAs. (1)(2)(3)(4). Dengue viruses (DENV-1 to -4), the most prevalent of all arthropod-borne viruses, infect approximately 390 million people per year (1); yellow fever virus (YFV), which causes life-threatening disease (5) has reemerged this year in Africa (6); Zika virus (ZIKV) is currently responsible for a pandemic in the Americas that has caused grave concern because of associations with birth defects and Guillain-Barré syndrome (3). KEYWORDS flavivirus, ribosomal proteins, tran...

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“…(Stegomyia) africanus (Theobald) mosquitoes and was passaged once in Ae . (Stegomyia) pseudoscutellaris (Theobald) cells, once in C6/36 cells, and 4 times in Vero cells [16]. …”

Section: Methodsmentioning

confidence: 99%

Vector Competence of American Mosquitoes for Three Strains of Zika Virus

et al. 2016

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In 2015, Zika virus (ZIKV; Flaviviridae; Flavivirus) emerged in the Americas, causing millions of infections in dozens of countries. The rapid spread of the virus and the association with disease outcomes such as Guillain-Barré syndrome and microcephaly make understanding transmission dynamics essential. Currently, there are no reports of vector competence (VC) of American mosquitoes for ZIKV isolates from the Americas. Further, it is not clear whether ZIKV strains from other genetic lineages can be transmitted by American Aedes aegypti populations, and whether the scope of the current epidemic is in part facilitated by viral factors such as enhanced replicative fitness or increased vector competence. Therefore, we characterized replication of three ZIKV strains, one from each of the three phylogenetic clades in several cell lines and assessed their abilities to be transmitted by Ae. aegypti mosquitoes. Additionally, laboratory colonies of different Culex spp. were infected with an American outbreak strain of ZIKV to assess VC. Replication rates were variable and depended on virus strain, cell line and MOI. African strains used in this study outcompeted the American strain in vitro in both mammalian and mosquito cell culture. West and East African strains of ZIKV tested here were more efficiently transmitted by Ae. aegypti from Mexico than was the currently circulating American strain of the Asian lineage. Long-established laboratory colonies of Culex mosquitoes were not efficient ZIKV vectors. These data demonstrate the capacity for additional ZIKV strains to infect and replicate in American Aedes mosquitoes and suggest that neither enhanced virus replicative fitness nor virus adaptation to local vector mosquitoes seems likely to explain the extent and intensity of ZIKV transmission in the Americas.

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Complete Genome Sequences of Five Zika Virus Isolates

Cited by 45 publications

References 13 publications

A Screen of FDA-Approved Drugs for Inhibitors of Zika Virus Infection

A Screen of FDA-Approved Drugs for Inhibitors of Zika Virus Infection

RPLP1 and RPLP2 Are Essential Flavivirus Host Factors That Promote Early Viral Protein Accumulation

Vector Competence of American Mosquitoes for Three Strains of Zika Virus

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