nsmb.3352-F2

Structure of the immature Zika virus at 9 Å resolution

The current Zika virus (ZIKV) epidemic is characterized by severe pathogenicity in both children and adults. Sequence changes in ZIKV since its first isolation are apparent when pre-epidemic strains are compared with those causing the current epidemic. However, the residues that are responsible for ZIKV pathogenicity are largely unknown. Here we report the cryo-electron microscopy (cryo-EM) structure of the immature ZIKV at 9-Å resolution. The cryo-EM map was fitted with the crystal structures of the precursor membrane and envelope glycoproteins and was shown to be similar to the structures of other known immature flaviviruses. However, the immature ZIKV contains a partially ordered capsid protein shell that is less prominent in other immature flaviviruses. Furthermore, six amino acids near the interface between pr domains at the top of the spikes were found to be different between the pre-epidemic and epidemic ZIKV, possibly influencing the composition and structure of the resulting viruses.

Cross-section of the immature ZIKV contoured to show the inner capsid shell.

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who

Fifth meeting of the Emergency Committee under the International Health Regulations (2005) regarding microcephaly, other neurological disorders and Zika virus

The Public Health Emergency of International Concern (PHEIC) declared by the Director-General of WHO has led the world to an urgent and coordinated response, providing the understanding that Zika virus infection and associated consequences represent a highly significant long-term problem that must be managed by WHO, States Parties and other partners in a way that other infectious disease threats are managed.

The EC originally recommended a PHEIC in February 2016 on the basis of an extraordinary cluster of microcephaly and other neurological disorders reported in Brazil, following a similar cluster in French Polynesia and geographic and temporal association with Zika virus infection which required urgent and coordinated and research. Because research has now demonstrated the link between Zika virus infection and microcephaly, the EC felt that a robust longer-term technical mechanism was now required to manage the global response.

As a result, the EC felt that Zika virus and associated consequences remain a significant enduring public health challenge requiring intense action but no longer represent a PHEIC as defined under the IHR. Many aspects of this disease and associated consequences still remain to be understood, but this can best be done through sustained research. The EC recommended that this should be escalated into a sustained programme of work with dedicated resources to address the long-term nature of the disease and its associated consequences.

The Committee reviewed the recommendations made at its previous meetings and agreed that WHO and partners had systematically addressed their advice. Furthermore, the EC reviewed and agreed to the WHO Zika transition plan outlined to establish the longer-term response mechanism which delivers the strategic objectives already identified in the Zika Strategic Response Plan.

Based on this advice, the Director-General declared the end of the Public Health Emergency of International Concern (PHEIC). The Director-General reissued the Temporary Recommendations from the previous meetings of the Committee which will be incorporated into the longer-term response mechanism. The Director-General thanked the Committee Members and Advisors for their advice over the past year.

who

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microcefalia

Description of 13 Infants Born During October 2015–January 2016 With Congenital Zika Virus Infection Without Microcephaly at Birth — Brazil

Congenital Zika virus infection can cause microcephaly and severe brain abnormalities. Congenital Zika syndrome comprises a spectrum of clinical features; however, as is the case with most newly recognized  teratogens, the earliest documented clinical presentation is expected to be the most severe. Initial descriptions of the effects of in utero Zika virus infection centered prominently on the finding of congenital microcephaly. To assess the possibility of clinical presentations that do not include congenital microcephaly, a retrospective assessment of 13 infants from the Brazilian states of Pernambuco and Ceará with   normal head size at birth and laboratory evidence of congenital Zika virus infection was conducted. All infants had brain abnormalities on neuroimaging consistent with congenital Zika syndrome, including decreased brain volume, ventriculomegaly, subcortical calcifications, and cortical malformations. The earliest evaluation occurred on the second day of life. Among all infants, head growth was documented to  have decelerated as early as 5 months of age, and 11 infants had microcephaly. These findings provide evidence that among infants with prenatal exposure to Zika virus, the absence of microcephaly at birth does not exclude congenital Zika virus infection or the presence of Zika-related brain and other abnormalities. These findings support the recommendation for comprehensive medical and developmental follow-up of infants exposed to Zika virus prenatally. Early neuroimaging might identify brain abnormalities related to congenital Zika infection even among infants with a normal head circumference.
microcefalia
testiculo-zika

Zika virus infection damages the testes in mice

Zika virus (ZIKV) infection of pregnant women can cause congenital malformations including microcephaly, which has focused global attention on this emerging pathogen. In addition to transmission by mosquitoes, ZIKV can be detected in the seminal fluid of affected males for extended periods of time and transmitted sexually. Here, using a mouse-adapted African ZIKV strain (Dakar 41519), we evaluated the consequences of infection in the male reproductive tract of mice. We observed persistence of ZIKV, but not the closely related Dengue virus (DENV), in the testis and epididymis of male mice, and this was associated with tissue injury that caused diminished testosterone and inhibin B levels, and oligospermia. ZIKV preferentially infected spermatogonia, primary spermatocytes, and Sertoli cells in the testis, resulting in cell death and destruction of the seminiferous tubules. Less damage was observed with a contemporary Asian ZIKV strain (H/PF/2013), in part because this virus replicates less efficiently in mice. The extent to which these observations in mice translate to humans remains unclear, but longitudinal studies of sperm function and viability in ZIKV-infected humans seem warranted.

 À esquerda, testículo de camundongo saudável, à direita, testículo de camundongo após uma infecção pelo vírus da zika  (Foto: Prabagaran Esakky)

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Zika virus in the female genital tract

In this Correspondence, we show that Zika virus RNA might be present in the female genital tract up to day 11 after symptoms onset, but with a genital clearance observed at day 17 before urine clearance. Zika virus clearance from the female genital tract needs to be assessed by large and longitudinal studies with infectiousness evaluation. These data should be used to change recommendations for prevention of sexual transmission of Zika virus.

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journal-pone-0164377-g001

A Lipidomics Approach in the Characterization of Zika-Infected Mosquito Cells: Potential Targets for Breaking the Transmission Cycle

Recent outbreaks of Zika virus in Oceania and Latin America, accompanied by unexpected clinical complications, made this infection a global public health concern. This virus has tropism to neural tissue, leading to microcephaly in newborns in a significant proportion of infected mothers. The clinical relevance of this infection, the difficulty to perform accurate diagnosis and the small amount of data in literature indicate the necessity of studies on Zika infection in order to characterize new biomarkers of this infection and to establish new targets for viral control in vertebrates and invertebrate vectors. Thus, this study aims at establishing a lipidomics profile of infected mosquito cells compared to a control group to define potential targets for viral control in mosquitoes. Thirteen lipids were elected as specific markers for Zika virus infection (Brazilian strain), which were identified as putatively linked to the intracellular mechanism of viral replication and/or cell recognition. Our findings bring biochemical information that may translate into useful targets for breaking the transmission cycle.

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Complete Genome Sequence of Zika Virus Isolated from Semen

Using an unbiased metagenomic sequencing approach, we report here the first complete genome sequence of ZIKV isolated from a clinical semen sample. Sequence data for the virus isolated from a clinical semen sample align well with other sequences of ZIKV from the outbreak, including those from the Caribbean region, where the patient acquired the infection. The characterization of ZIKV isolated from semen samples will help improve our understanding of possible viral polymorphisms resulting from infection in different cellular environments. The isolated virus will be available imminently from the National Collection of Pathogenic Viruses and the European Virus Archive.

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journal-pntd-0005017-t001

DNA Microarray Platform for Detection and Surveillance of Viruses Transmitted by Small Mammals and Arthropods

In this study, we describe a DNA microarray platform that can be used for screening all viruses transmitted by small mammals and arthropods (SMAvirusChip) with nucleotide sequences that have been deposited in the GenBank. SMAvirusChip was designed with more than 15,000 oligonucleotide probes (60-mers), including viral and control probes. Two SMAvirusChip versions were designed: SMAvirusChip v1 contains 4209 viral probes for the detection of 409 viruses, while SMAvirusChip v2 contains 4943 probes for the detection of 416 viruses. SMAvirusChip was evaluated with 20 laboratory reference-strain viruses. These viruses could be specifically detected when alone in a sample or when artificially mixed within a single sample. The sensitivity of SMAvirusChip was evaluated using 10-fold serial dilutions of dengue virus (DENV). The results showed a detection limit as low as 2.6E3 RNA copies/mL. Additionally, the sensitivity was one log10 lower (2.6E2 RNA copies/mL) than quantitative real-time RT-PCR and sufficient to detect viral genomes in clinical samples. The detection of DENV in serum samples of DENV-infected patients (n = 6) and in a whole blood sample spiked with DENV confirmed the applicability of SMAvirusChip for the detection of viruses in clinical samples. In addition, in a pool of mosquito samples spiked with DENV, the virus was also detectable. SMAvirusChip was able to specifically detect viruses in cell cultures, serum samples, total blood samples and a pool of mosquitoes, confirming that cellular RNA/DNA did not interfere with the assay. Therefore, SMAvirusChip may represent an innovative surveillance method for the rapid identification of viruses transmitted by small mammals and arthropods.

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journal-pntd-0004978-g001

Nonstructural Proteins Are Preferential Positive Selection Targets in Zika Virus and Related Flaviviruses

ZIKV encodes a polyprotein that is processed to produce three structural and seven nonstructural (NS) proteins. We investigated the evolution of the viral polyprotein in ZIKV and in related flaviviruses (DENV, Spondweni virus, and Kedougou virus). After accounting for saturation issues, alignment uncertainties, and recombination, we found evidence of episodic positive selection on the branch that separates DENV from the other flaviviruses. NS1 emerged as the major selection target, and selected sites were located in immune epitopes or in functionally important protein regions. Three of these sites are located in an NS1 region that interacts with structural proteins and is essential for virion biogenesis. Analysis of the more recent evolutionary history of ZIKV lineages indicated that positive selection acted on NS5 and NS4B, this latter representing the preferential target. All selected sites were located in the N-terminal portion of NS4B, which inhibits interferon response. One of the positively selected sites (26M/I/T/V) in ZIKV also represents a selection target in sylvatic DENV2 isolates, and a nearby residue evolves adaptively in JEV. Two additional positively selected sites are within a protein region that interacts with host (e.g. STING) and viral (i.e. NS1, NS4A) proteins. Notably, mutations in the NS4B region of other flaviviruses modulate neurovirulence and/or neuroinvasiveness. These results suggest that the positively selected sites we identified modulate viral replication and contribute to immune evasion. These sites should be prioritized in future experimental studies. However, analyses herein detected no selective events associated to the spread of the Asian/American ZIKV lineage.

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journal-pntd-0004993-g001

Culex quinquefasciatus from Rio de Janeiro Is Not Competent to Transmit the Local Zika Virus

The southern house mosquito Cx. quinquefasciatus from Rio de Janeiro was not competent to transmit local strains of ZIKV. Thus, there is no experimental evidence that Cx. quinquefasciatus likely plays a role in the ZIKV transmission. Consequently, at least in Rio, mosquito control to reduce ZIKV transmission should remain focused on Ae. aegypti.

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