Zika Virus - ACS Publications - American Chemical Society

Review pubs.acs.org/journal/aidcbc

Zika Virus: Emergence, Phylogenetics, Challenges, and Opportunities Maaran M. Rajah,† Ryan D. Pardy,† Stephanie A. Condotta,† Martin J. Richer,*,†,‡ and Selena M. Sagan*,†,‡ †

Department of Microbiology and Immunology and ‡Microbiome and Disease Tolerance Centre (MDTC), McGill University, Montréal, Québec, Canada H3A 2B4 ABSTRACT: Zika virus (ZIKV) is an emerging arthropodborne pathogen that has recently gained notoriety due to its rapid and ongoing geographic expansion and its novel association with neurological complications. Reports of ZIKV-associated Guillain−Barré syndrome as well as fetal microcephaly place emphasis on the need to develop preventative measures and therapeutics to combat ZIKV infection. Thus, it is imperative that models to study ZIKV replication and pathogenesis and the immune response are developed in conjunction with integrated vector control strategies to mount an efficient response to the pandemic. This paper summarizes the current state of knowledge on ZIKV, including the clinical features, phylogenetic analyses, pathogenesis, and the immune response to infection. Potential challenges in developing diagnostic tools, treatment, and prevention strategies are also discussed. KEYWORDS: Zika virus, Guillain−Barré syndrome, fetal microcephaly

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INTRODUCTION

TRANSMISSION AND CLINICAL FEATURES OF ZIKV INFECTION ZIKV is an arbovirus that belongs to the Flavivirus genus of the Flaviviridae family. Viral transmission occurs through both sylvatic and urban cycles involving a variety of Aedes species mosquitos and either nonhuman primates or humans as the amplifying reservoir, respectively. It is not yet clear whether other mammals or mosquito species can serve as an amplifying reservoir, but viral replication in cell culture has been demonstrated in a variety of animal cell lines.9 Recent papers have also described ZIKV replication in testicular tissue and excretion in semen, suggesting that sexual transmission is also a route of ZIKV infection.7,10−12 Although transmission of ZIKV through breast milk has not been documented, it has been demonstrated to contain high viral loads, suggesting this may represent another potential route of transmission.13,14 A deeper understanding of the amplifying reservoirs for ZIKV and routes of transmission will be critical to contain the ongoing epidemic and prevent further spread. ZIKV replication is first thought to occur in human primary dermal fibroblasts, epidermal keratinocytes, and immature dendritic cells at the site of inoculation.15 From the site of the mosquito bite, ZIKV spreads to the draining lymph node, where it is amplified and disseminated through the bloodstream to peripheral tissues and visceral organs. ZIKV is first detectable in the blood within the first 10 days of infection, with peak viral

Zika virus (ZIKV) is an emerging mosquito-borne pathogen that has recently become a significant global health concern due to its rapid geographical expansion and pathogenesis associated with infection. The virus was initially described in 1947 in the Zika forest region of Uganda, where it was isolated from the blood of sentinel rhesus macaques.1 Serological surveys conducted in West Africa demonstrated the presence of ZIKV antibodies in human populations; however, the first human infection was not reported until 1964.2,3 For the latter half of the 20th century the virus remained in relative obscurity with only isolated human cases reported until the first serious outbreak in 2007.4 During this outbreak, over 73% of the population of Yap Island, Federated States of Micronesia, became infected with ZIKV in a period of 4 months.5,6 This was followed by a major outbreak in 2013 in French Polynesia; together, these outbreaks represented the first significant transmission of ZIKV outside its original endemic regions.6 Since then, ZIKV has been introduced into the Western Hemisphere, causing an ongoing epidemic in South America, with localized epidemics in Argentina, Colombia, Brazil, El Salvador, Guatemala, Paraguay, and Venezuela, as well as recent outbreaks in the southern United States and Singapore.6−8 Although ZIKV typically causes a mild, self-limiting febrile illness, its explosive spread across South America and its recent association with more severe pathogenesis make ZIKV infection a serious public health concern that must be rapidly addressed through a concerted collaborative effort between researchers, clinicians, and public health officials alike. © 2016 American Chemical Society

Special Issue: Host-Pathogen Interactions Received: September 14, 2016 Published: October 5, 2016 763

DOI: 10.1021/acsinfecdis.6b00161 ACS Infect. Dis. 2016, 2, 763−772

ACS Infectious Diseases

Review

Figure 1. Phylogenetic analysis of ZIKV. Translated amino acid sequences of 94 ZIKV polyproteins were aligned using ClustalW. Trees were constructed by neighbor joining of pairwise amino acid distances with the program MEGA7 (according to the distance scale provided). Bootstrap resampling was used to determine robustness of branches; values of ≥50% (from 1000 replicates) are shown. Human (black circles), monkey (gray circles), and mosquito (open circles) isolates are indicated. Isolate name, country of origin, and year of isolation, as well as the unique accession numbers for each sequence, are indicated.

loads coinciding with the onset of symptoms, which typically present between 2 and 12 days postinfection.16−18 ZIKV

infection has been reported to cause a self-limiting illness that is mostly asymptomatic, but can present with mild symptoms in 764



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up to 20% of cases.19 These symptoms typically include fever, maculopapular rash, headache, joint and muscle pain, fatigue, and conjunctivitis.5,6,16 During the Yap Island outbreak, other symptoms including myalgia, headaches, retro-orbital pain, edema, and vomiting were also reported.5 The presentation of a mild febrile illness can be misdiagnosed as Dengue or Chikungunya virus infection due to their similar clinical presentation.20 In areas of co-circulation of these pathogens, multiple infections are likely very common;21,22 however, it remains to be seen whether there are synergistic effects due to co-infection, vaccination, or past infections.23−25 In the recent outbreaks, beginning with the 2013 French Polynesia outbreak, ZIKV has been linked to an increase in more severe neurological complications including Guillain−Barré syndrome and fetal microcephaly. The factors contributing to this sudden rise in ZIKV-associated neurological symptoms currently remain unexplained, and research efforts are directed at identifying host, pathogen, and environmental factors linked to these complications. Guillain−Barré Syndrome. Guillain−Barré syndrome is a severe neurological autoimmune disease causing acute or subacute flaccid paralysis that is attributable to peripheral nerve damage.26,27 During the French Polynesia outbreak, there were 48 reported cases of Guillain−Barré syndrome, and 88% of the affected patients reported a symptomatic ZIKV infection prior to the onset of neurological symptoms; this was comparatively higher than the 5 cases per annum reported over the previous 4 years.27 A case-controlled study on 42 of these patients demonstrated that all of them had neutralizing antibodies directed against ZIKV.27 Although none of these patients died, 50% of them were still unable to walk without assistance 3 months after discharge. A similar pattern was observed in the current epidemic in Latin America and the Caribbean, where the incidence of Guillain−Barré syndrome in seven different countries was reported to be 2−9.8-fold higher than baseline.28 Although fatalities among Guillain−Barré syndrome patients are rare, the severity and burden of the disease on the health care system as well as to the affected patients and their families suggest that research is needed to better understand the underlying pathology and improve diagnosis and treatment.26 Fetal Microcephaly. One of the most alarming aspects of the recent outbreaks has been the association of ZIKV infection with an increase in congenital malformations including fetal microcephaly (a neurodevelopmental disorder that results in malformation of the brain and head), which can result in severe life-long limitations for the child and family.29 Reports from the Brazilian Ministry of Health suggest that there is a 20-fold increase in the incidence of microcephaly that coincides with the current ZIKV epidemic.30 Recent studies have strongly linked ZIKV infection during pregnancy to microcephaly, including the detection of viral RNA in amniotic fluid, ZIKVspecific IgM antibodies in the cerebrospinal fluid of microcephalic neonates (indicative of active central nervous system infection), and reports that ZIKV attenuates growth of human neural progenitor cells.6,31−33 Although questions remain about the type of exposure and whether symptomatic or asymptomatic infection poses the greatest risk to the fetus, the first trimester of pregnancy has been identified as the gestational period at major risk for microcephaly.34,35 This is further supported by a recent study that demonstrated ZIKV-induced apoptosis in first trimester human trophoblasts as well as detrimental effects on trophoblast differentiation.36 In addition

to microcephaly, a number of other malformations have been reported in fetuses and newborns with congenital ZIKV infection, including intrauterine growth restriction, brain atrophy, cerebral and placental calcifications, arthrogryposis, and retinal and optic nerve abnormalities.37−40 Although recent research has started to decipher some of the mechanisms through which ZIKV can lead to fetal abnormalities, a concerted effort is required to further understand all of the factors associated with ZIKV-induced pathogenesis. Success will be dependent on a collaborative multidisciplinary research to assemble epidemiological data along with the establishment of models to study host−pathogen interactions that ultimately shape ZIKV pathogenesis.

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ZIKV GENOME AND PHYLOGENETIC ANALYSES Similar to other clinically relevant human pathogens belonging to this family (e.g., yellow fever, West Nile, and Dengue viruses), ZIKV is a single-stranded, positive-sense RNA virus with a single open reading frame flanked by highly structured 5′ and 3′ untranslated regions (UTRs). The genome encodes a single polyprotein that is cleaved by host and viral proteases into the structural [capsid (C), premembrane protein (prM), and envelope (E)] and nonstructural proteins (NS1, NS2A, NS2B, NS3, NS4A, 2K, NS4B, and NS5).19,41,42 The structural proteins form the virion particle, whereas the nonstructural proteins participate in polyprotein processing, viral RNA replication, virion assembly, and evasion of the host immune response. Phylogenetic analyses have established that there are two main ZIKV lineages, African and Asian (Figure 1).41−43 Notably, all of the contemporary human strains have greater sequence homology to the mosquito strain P6-740 (Malaysia, 1966) than the African strains, suggesting that the currently circulating strains evolved from the Asian lineage, anchored by P6-740.42,43 In addition, all of the strains identified in the 2015−2016 epidemic are more closely related to the H/PF/ 2013 French Polynesia strain than the FSM/2007 Micronesia strain, suggesting that these sublineages may have evolved independently from a common ancestor (Figure 1). Interestingly, the current ZIKV outbreak in Singapore is of the Asian lineage, but sequence analyses suggest that it evolved independently from a strain that was already circulating in Southeast Asia, rather than being derived from an imported case from the ongoing South American outbreak. Comparative analyses of historical ZIKV strains in both in vitro and in vivo models is likely to answer important questions regarding the emergence and pathogenesis of ZIKV during the current outbreaks. Comparative genetic analyses suggest that there are several amino acid polymorphisms that are common to the Asian lineage isolates with known clinical outcomes when compared with the African (MR766, CDC reference strain) and P6-740 strains.42,43 The recent acquisition of these amino acid polymorphisms could potentially contribute to the increased pathogenesis and dissemination seen in the current outbreaks. On the basis of their locations within the ZIKV polyprotein, these mutations are predicted to contribute to ZIKV infection, replication, pathogenesis, and the immune response to infection.42,43 Amino acid polymorphisms in the prM, E, and NS1 proteins may contribute to infectivity and the immune response, whereas those in NS2A and NS3 are likely to affect polyprotein processing and replication. Interestingly, the NS4B and NS5 proteins contain large clusters of amino acid 765



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polymorphisms.42,43 This may be of particular interest because NS4B is implicated in replication, pathogenesis, and antiviral signaling, whereas the NS5 protein is the viral RNA-dependent RNA polymerase responsible for viral RNA synthesis.42,43 Although it is clear that ZIKV has undergone significant evolution since its discovery, little is known about how these recently acquired nucleotide and amino acid polymorphisms have contributed to the increased pathogenesis and rapid dissemination of ZIKV in the current outbreaks.42,43 These studies have been hampered by the lack of ZIKV reverse genetics systems and suitable small animal models (discussed in more detail below).

ment) generated from human induced pluripotent stem cells.33,48−50 These studies indicate that ZIKV can infect hNPCs with high efficiency, resulting in increased cell death and dysregulation of the cell cycle, as well as impaired growth and morphogenesis of healthy neurospheres.33 Furthermore, infected hNPCs release infectious viral particles, presenting a challenge for the development of therapeutics to halt or block the impact of infection.33,48−50 Importantly, these findings suggest a potential mechanism of ZIKV-induced microcephaly as hNPCs are essential for the development of the cortex and brain. Whereas these cell culture approaches are of great importance in understanding ZIKV infectivity, viral fitness, replication, and antiviral responses, these approaches do not take into account the complexity of host−pathogen interactions and need to be complemented by animal models of infection. Animal Models. The establishment of animal models is extremely important for understanding ZIKV pathogenesis and the immune response to infection, as well as for the design and testing of effective vaccine strategies and therapeutics. Nonhuman primates are similar to humans in terms of gestation and fetal development and therefore may provide important translational insights. To date, the majority of nonhuman primate ZIKV studies have focused on viral dissemination and vaccine protection;51,52 however, a recent study demonstrated that subcutaneous ZIKV infection of a pregnant pigtail macaque results in arrested fetal brain development and neuro-invasion.53 Future studies in these models are likely to further our understanding of ZIKV fetal pathogenesis. However, nonhuman primates present a number of logistical challenges that make them less suitable for certain research avenues than other small animal models. The use of the wild-type (WT) C57BL/6 or 129 Sv/Ev mouse strains to create a model of ZIKV pathogenesis has been hampered by the apparent lack of infectivity of ZIKV in these mice. Indeed, it has been shown in vitro that although the ZIKV NS5 protein is capable of impeding IFN signaling in human cells by binding to the STAT2 protein, it is unable to do so in murine cells.54 To address this, the majority of mouse models have used mice lacking the IFN-α/β receptor (IFNAR; IFNAR−/− or A129 mice), both IFNAR and the IFN-γ receptor (IFNGR; AG129 mice), or Irf3−/−Irf5−/−Irf7−/− triple-knockout mice that produce limited type I IFN (Table 1).10,55−57 The ability of ZIKV to cause severe pathogenesis and even fatal infection in many of these models emphasizes the importance of a robust type I IFN response in the innate immune response to ZIKV.10,55−57 Analyses of viral dissemination and pathogenesis within these mice have also highlighted ZIKV’s capacity to infect and replicate within immune privileged sites such as the reproductive organs, eyes, and brain, similar to reports in human patients.6,12,58−61 Mice deficient in IFNAR signaling have also been used to address the effects of ZIKV infection on fetal development. After subcutaneous infection of pregnant IFNAR−/− mice, ZIKV was detectable in both the placenta and fetal brain, which led to intrauterine growth restriction and fetal demise.58 Similarly, a recent paper demonstrated that intravaginal infection of IFNAR−/− dams mated with WT males led to total fetal resorption when infection occurred early in pregnancy.59 Although structural differences between the human and mouse placenta must be considered, these studies provide an important first step in understanding the ability of ZIKV to transverse the placenta, as well as its tropism for neural progenitor cells in the developing brain.62 Intriguingly, intravaginal infection of pregnant WT mice still caused

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UNDERSTANDING ZIKV PATHOGENESIS AND THE IMMUNE RESPONSE TO INFECTION Most of our knowledge of the ZIKV life cycle has been extrapolated from our knowledge of related flaviviruses. As such, much remains to be determined regarding ZIKV replication, cell tropism, transplacental transmission, pathogenesis and the immune response to infection. Furthermore, it is unclear what factors have contributed to the explosive spread and increased virulence of ZIKV in the recent and ongoing epidemics. The development of genetic tools and experimental systems, including mosquito transmission models, reverse genetics systems, and animal models, will be crucial to improve our understanding of ZIKV transmission, replication and pathogenesis and the immune response to infection. Furthermore, these experimental systems will be critical to facilitate the development of novel vaccine and therapeutic strategies. Cell Culture Systems. In vitro and ex vivo models are useful for dissecting the molecular mechanisms of viral infection, fitness, replication, and host−virus interactions. To date, in vitro studies have been focused on determining suitable cell types for ZIKV infection and replication as well as those involved in transplacental transmission and neural damage to investigate ZIKV pathogenesis. The link between ZIKV infection and fetal microcephaly has been demonstrated by detection of viral RNA in the placenta, amniotic fluid, and brain, as well as ZIKV IgM-specific antibodies in the cerebrospinal fluid of microcephalic neonates.6,29,31−33,44 Recent studies suggest that ZIKV is able to infect and replicate in primary human placental cells (cytotrophoblasts, endothelial cells, fibroblasts, and Hofbauer cells) from mid to late gestation as well as villus explants from first-trimester human placentas, suggesting two possible routes of ZIKV transmission to the fetus (placental and paraplacental).45,46 Furthermore, ZIKV replication in Hofbauer cells (placental macrophages) was associated with induction of type I interferons (IFN), proinflammatory cytokines, and antiviral gene expression, but minimal cytopathic effects, suggesting that these cells may allow ZIKV to gain access to the fetal compartment and could play a role in viral dissemination.46 In contrast, primary human trophoblasts (the barrier cells of the placenta) from full-term placentas are refractory to ZIKV infection and produce type III IFN that are postulated to protect trophoblast and nontrophoblast cells from infection during later stages of pregnancy.47 Several groups have investigated the link between ZIKV infection and neural pathogenesis in vitro using human neural progenitor cells (hNPCs), neurons, and cerebral organoids (three-dimensional, self-organized, stem-cell-derived models that recapitulate the first trimester of human neurodevelop766



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introduce specific mutations as well as generate reporter viruses that will facilitate antiviral drug discovery efforts. Together, these advances will significantly accelerate the capacity of the research community to understand ZIKV molecular biology, pathogenesis, and the immune response and will aid in the development of tools to counter the growing threat of ZIKV infection.

Table 1. Murine Models of ZIKV Infection: Opportunities and Challenges

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CHALLENGES FOR ZIKV RESEARCH Vector Control. The concept of mosquito vector control has been suggested for many years as an approach to control vector-borne infections. However, many challenges arise that can hamper the implementation of effective control strategies.68 For example, the mosquito life cycle is a major determinant for executing successful vector control initiatives. The primary mosquito vector for ZIKV transmission is Aedes aegypti, and recently Aedes albopictus has also been implicated in transmission.69−72 Although both of these species belong to the Aedes genus, they have different habitat and behavioral characteristics. For instance, Aedes aegypti species bite during the day, typically rest indoors, and lay their eggs in artificial containers in and around homes,68 whereas Aedes albopictus species bite in the early morning and late afternoon, rest outdoors, and prefer to lay their eggs in natural containers such as tree holes and ground pools.73 These individualistic features need to be considered when vector control approaches are employed; as such, entomological surveillance is imperative for efficacious vector control initiatives. Prevention targeted at different mosquito life stages is one control method that can be easily implemented by individuals at home and through public health community awareness. Mosquitoes go through four distinct and separate life stages: egg, larvae, pupae, and adult. Monitoring areas of mosquito populations and eliminating breeding grounds is the first step. Individuals at home can remove standing water in receptacles in and around the home, which will eliminate mosquito eggs, larvae, and pupae. Spraying with insecticides will kill adult mosquitoes, and because of their unique resting preferences, insecticides should be targeted to the appropriate areas to kill adult Aedes aegypti and Aedes albopictus, thus ultimately reducing virus transmission. Another aspect to consider is the possibility of overwintering and vertical transmission.74 Mosquito eggs can survive dry seasons (desiccation) and cold periods (diapause), facilitating long-term mosquito survival.75 During the change of seasons (shorter days and colder temperatures), Aedes albopictus is able to lay diapausing eggs, ensuring survival until the next hatching period.75 A consequence of this behavior is that there is a possibility that ZIKV-infected females could vertically transmit ZIKV to progeny. In fact, vertical transmission of ZIKV has already been documented in Aedes aegypti, suggesting a potential mechanism for virus persistence during adverse conditions.76 Thus, although vector control is an attractive option to reduce ZIKV transmission, there are a large number of variables that need to be considered to implement effective control protocols. Biological control and genetic manipulation represent another set of tools that can be used for vector control. The bacterium Wolbachia has been demonstrated to reduce the ability of mosquitoes to transmit viruses to humans.77,78 When introduced into Aedes aegypti populations, a symbiotic strain of Wolbachia reduces ZIKV replication within the mosquito, delaying virus dissemination to the mosquito salivary glands and therefore reducing vector competence.77,78 Genetic

intrauterine growth restriction in the absence of systemic viremia.59 Together, these models provide excellent tools for interrogating ZIKV pathogenesis and will be extremely useful for testing potential therapeutics. Despite the challenges associated with infection of WT mice, there is still an urgent need for immunocompetent mouse models for ZIKV infection. The lack of an intact type I IFN response in the models described above precludes in-depth analyses of the immune response to ZIKV infection. In addition to a role in innate immune responses, type I IFN plays a critical role in the induction of an optimal adaptive immune response, including CD8+ T cells, which are required for clearance of intracellular pathogens.63 To date, only one immunocompetent mouse model has been proposed, which used WT SJL mice (Table 1).50 In this strain, pregnant WT mice infected with a Brazilian ZIKV isolate gave birth to pups with severe intrauterine growth restriction, ocular deformities, and reduced cell number and cortical thickness in the brain (symptoms associated with microcephaly in humans).50 No such defects were observed in pregnant WT C57BL/6 mice, suggesting there may be a genetic influence to ZIKV-induced microcephaly.50 Analyses of the ZIKV immune response in both C57BL/6 and SJL mice will be of interest to determine specific differences that dictate the apparent increased susceptibility of SJL mice to ZIKV infection. In addition, immunocompetent mouse models will be critical to understand whether newly acquired viral polymorphisms contribute to the capacity of ZIKV to counter host immune defenses. Until recently, both in vitro and in vivo studies of ZIKV have relied on serial passage of ZIKV isolates in suckling mice or cell culture. However, these systems are not suitable for the dissection of viral polymorphisms (limited to those mutations present in viral isolates) and may result in the selection of viral mutants (e.g., cell culture adaptations). Understanding the contribution of viral polymorphisms to the explosive transmission and increased pathogenesis of currently circulating ZIKV strains has been hampered by the lack of ZIKV reverse genetics models; however, several groups have now reported the development of full-length infectious cDNA clones.64−67 These ZIKV reverse genetic systems will allow researchers to 767



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inhibition of several flaviviruses, including ZIKV, suggesting that these compounds might represent lead candidates for the development of specific ZIKV antivirals.90−92 An alternative pharmacologic strategy is to perform drug-repurposing screens of existing clinical compounds for their potential anti-ZIKV activity. This approach has been undertaken for other emerging viruses, and two such screens have now been reported for ZIKV.93,94 These studies each screened hundreds of clinically approved drugs, clinical trial drug candidates, and pharmacologically active compounds that exhibited anti-ZIKV activity or were neuroprotective in nature.93,94 Several active compounds were identified in both studies that were further validated in ZIKV-infected human neural stem cells and primary amnion cells, demonstrating the efficacy of such screening strategies to identify lead compounds for anti-ZIKV drug development. As an alternative to small-molecule-based inhibitors, therapeutic antibodies could also be developed to prevent or treat ZIKV infections. Neutralizing antibodies have already been studied in the context of Dengue virus infection and have demonstrated reduction in viral loads in a variety of experimental systems.95 In addition to reducing viremia in the mother, the ability of IgG antibodies to cross the placenta suggests that ZIKV-neutralizing antibodies could reach the fetus, protecting against infection and fetal microcephaly. However, the use of anti-ZIKV antibodies should be carefully selected to minimize side effects and potential disease enhancement.96 No matter the strategy, the major challenge in the development of ZIKV inhibitors will be the time and caution required to critically evaluate the efficacy and toxicity for use in pregnant women, who represent the highest risk population. Vaccines. A variety of different vaccine platforms are currently being explored for ZIKV. These include subunit and DNA-based vaccines as well as the inactivated or live attenuated vaccines. A recent study reported efficacy of both plasmid DNA- and rhesus adenovirus vector-based vaccines, both of which expressed the ZIKV prM and E proteins, which were able to successfully confer full protection against ZIKV challenge.51 Although the time to development for a subunit or DNA-based vaccine is likely to be shorter than inactivated or live attenuated vaccine strategies, this approach is likely to require multiple doses to achieve protective immunity. In addition, this approach is likely to induce only an antibody response, thus making it more susceptible to being countered by viral evolution. In contrast, live attenuated approaches typically elicit both antibody and cell-mediated immunity and are thus likely to provide more robust protection. In line with this, a recent study demonstrated that a purified inactivated virus vaccine was indeed able to confer full protection against the Brazilian and Puerto Rican strains of ZIKV in rhesus macaques.51 Although each of these approaches has merit, given that there are already licensed inactivated or live attenuated vaccines for several flaviviruses, it is likely that one of these approaches will have the greatest likelihood of success.97 The major complications surrounding successful vaccine development arise from distinct features of ZIKV infection and include the low incidence of clinical presentation, short period of viremia, the risk of neurological symptoms, and the risk of sexual transmission.98 Further complications for vaccine development could result from the close phylogenetic relationship between ZIKV and other arthropod-borne flaviviruses.99 Pre-existing antibodies to these related viruses could attenuate

modification of mosquitos is another strategy that has been proposed. The introduction of the OX513A gene into the mosquito genome results in normal development of larvae; however, these genetically modified mosquitos die before adulthood, potentially reducing the risk of virus transmission.79−82 The possibility of environmental damage and a general public distrust of genetically modified organisms are two of the current limitations hindering the widespread implementation of vector control strategies in ZIKV-affected areas.83 However, the effectiveness of such strategies has been demonstrated in recent field studies, where the sustained release of OX513A Aedes aegypti males successfully reduced the local Aedes aegypti population by 95% in Bahia, Brazil.84 The future of vector control will thus require an integrated approach where basic strategies such as eliminating breeding grounds and larval source management will need to be implemented in conjunction with more sophisticated strategies, including biocontrol and genetic manipulation.83 Diagnostics. Definitive diagnosis of ZIKV infection is challenging due to the similar symptomology and broad crossreactivity of Flavivirus antibodies induced during infection. As such, reliable diagnosis can be achieved only by laboratory assays. At present, laboratory diagnosis of ZIKV infection relies on isolation of the virus in culture, detection of viral RNA in blood or other biological samples, or serologic testing. Thus, a major challenge in ZIKV research is the development of diagnostic assays that can rapidly and definitively diagnose ZIKV infection. Although the gold standard to diagnose viral infections is isolation of the virus in culture, this requires sufficient viral load, appropriate timing of sample collection, and significant resources to perform. This renders this approach difficult to implement in the field. Detection of viral RNA using RT-PCR is the most widespread diagnostic assay used to detect ZIKV in blood, urine, saliva, or semen specimens.85−87 RT-PCR-based assays have the best sensitivity during the first week of symptom onset while patients are still viremic;87 however, viral RNA can still be detected in samples several months after the onset of symptoms.11,87−89 Both in-house and commercial assays have been developed for serologic testing for ZIKV IgM and IgG antibodies in serum.85 However, many ZIKV immunoassays have significant cross-reactivity with heterologous flaviviruses from previous infections or vaccination.18,85 Positive results from enzymelinked immunosorbent assays (ELISA) or immunofluorescence assays should be confirmed by neutralization assays; however, in patients with secondary Flavivirus infections, neutralization assays may not be conclusive due to the induction of broadly neutralizing antibodies from previous infections.18,85 This is a particular concern in regions of South America, where other flaviviruses, such as Dengue virus, are endemic and have infected the large majority of the population. Thus, the development of more specific antigens is likely required to improve serologic diagnosis of ZIKV infection in the future. Therapeutics. To date, there are no clinically approved antiviral therapeutics for flaviviruses. However, some of the experience gained from drug discovery efforts for Dengue virus and related viruses can be applied to ZIKV. Both viral infection models and viral enzyme assays will be useful in identifying ZIKV-specific inhibitors from small-molecule compound libraries. In fact, nucleotide/nucleoside-based inhibitors, such as 7-deaza-2′-C methyladenosine, T-705 (favipiravir), and 2′-Cmethylated nucleosides, have already shown promise for 768



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*(M.J.R.) Mail: McGill University, 3775 University Street, Room 406A, Montréal, QC, Canada H3A 2B4. E-mail: martin.j. [email protected].

optimal adaptive immune responses and hamper the efficacy of vaccines in Flavivirus endemic populations and may result in antibody-dependent enhancement (where cross-reactive antibodies from previous Flavivirus infection or vaccination can enhance subsequent infections).96,99 Two recent studies suggest that cross-reactive antibodies produced in response to prior Dengue virus infection can indeed exacerbate ZIKV infection.96,100 As such, vaccination efforts must carefully consider the risk of antibody-dependent enhancement and assess Flavivirus serostatus in test populations.98

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by start-up funds from McGill University (S.M.S. and M.J.R.) as well as operating funds from the Fonds de Recherche du Québec Nature et Technologies (S.M.S.). S.M.S. is a Tier II Canada Research Chair in RNA Biology and Viral Infections. M.J.R. received salary support from the Fonds de Recherche du Québec Santé − ChercheursBoursiers Junior 1. M.M.R. thanks the McGill University Faculty of Medicine Max E. Binz Fellowship for graduate training. R.D.P. thanks the Natural Sciences and Engineering Research Council of Canada (NSERC) Canada Graduate Scholarship − Masters (CGS-M) for graduate support.

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SUMMARY AND CONCLUSIONS From its initial isolation in the mid-20th century in Uganda, ZIKV remained in relative obscurity until recent outbreaks in Micronesia (2007), French Polynesia (2013), and Latin America (ongoing) brought it to the forefront of global public health consciousness. Whereas ZIKV infection typically presents as a mild febrile illness, recent epidemics have been associated with novel pathogenesis including Guillain−Barré syndrome and fetal microcephaly. The rapid mobilization of the scientific community has already led to several advances in understanding the pathogenesis of ZIKV and how this may be linked to these novel neurological complications. Furthermore, phylogenetic analyses suggest that viral evolution may have played a role in the rapid emergence and pathogenesis observed in the recent outbreaks. Comparative genetic analyses and reverse genetic models, as well as in vitro and in vivo models, are likely to provide more insight into how host−pathogen interactions and viral evolution have shaped ZIKV transmission and the pathogenesis associated with the current outbreaks. In addition, this outbreak represents a unique opportunity to gain further insight into the factors that can influence the capacity of emerging viruses to establish epidemics. Despite the rapid mobilization of the scientific community, there remain a number of outstanding questions that need to be addressed: Did viral evolution lead to changes that resulted in increased infectivity and pathogenesis of ZIKV? Are there host genetic factors associated with the increase in neurological symptoms such as Guillain−Barré syndrome? Has the prevalence of infection with heterologous f laviviruses in endemic regions contributed to the sudden rise in pathogenesis? What are the correlates of immune protection and are these somehow compromised in pregnant women? The answers to these questions will be critical for the development of novel therapeutic and vaccine strategies aimed at preventing ZIKV infection. Significant research efforts will be required to curb the growing global threat posed by ZIKV infection. The rapid response from the research community has already provided several in vitro and in vivo models that will help provide a greater understanding of viral transmission, replication, pathogenesis, and the immune response to infection. Future research efforts are thus likely to be focused on implementation of appropriate vector control strategies and development of novel diagnostic tools and antivirals, as well as design and testing of ZIKV vaccine strategies.

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REFERENCES

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AUTHOR INFORMATION

Corresponding Authors

*(S.M.S.) Mail: McGill University, 3775 University Street, Room 608, Montréal, QC, Canada H3A 2B4. E-mail: selena. [email protected]. 769



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