Vertical Transmission Of Zika Virus Research Articles

Vertical transmission of Zika virus and perinatal microcephaly

Zika virus (ZIKV) is an arthropod-borne virus (arbovirus) transmitted primarily by Aedes mosquitoes. ZIKV can be transmitted to humans by non-vector borne mechanisms such as sexual intercourse, maternal-foetal transmission or blood transfusion. In 2015, ZIKV emerged in the Americas, and spread to 87 countries and territories with autochthonous transmission, distributed across four of the six WHO regions. Most ZIKV infections in pregnancy are asymptomatic, but mother to child transmission of the virus can occur in 20 to 30% of cases and cause severe foetal and child defects. Children exposed to ZIKV while in utero might develop a pattern of structural anomalies and functional disabilities secondary to central nervous system damage, known as congenital Zika syndrome, and whose most common clinical feature is microcephaly. Normocephalic children born to mothers with ZIKV infection in pregnancy, and with no observable Zika-associated birth defects, may also present with later neurodevelopmental delay or post-natal microcephaly. Screening and detection of ZIKV infection in pregnancy is essential, because most women with ZIKV infection are asymptomatic and clinical manifestations are non-specific. However, the diagnosis of ZIKV infection poses multiple challenges due to limited resources and scarce laboratory capabilities in most affected areas, the narrow window of time that the virus persists in the bloodstream, the large proportion of asymptomatic infections, and the cross-reactivity with other flaviviruses such as Dengue virus (DENV). Molecular methods (RT-PCR) are the most reliable tool to confirm ZIKV infection, as serodiagnosis requires confirmation with neutralization tests in case of inconclusive or positive serology results. Prenatal ultrasound assessment is essential for monitoring foetal development and early detection of possible severe anomalies. A mid- and long-term follow-up of children exposed to ZIKV while in utero is necessary to promptly detect clinical manifestations of possible neurological impairment.Tweetable abstract: Zika virus infection during pregnancy is a cause of pregnancy loss and disability in children. Protection against mosquito bites, access to sexual and reproductive health services, prompt screening and detection of ZIKV infection in pregnancy, and prenatal ultrasound monitoring are key control strategies whilst a vaccine is not available.

A CRISPR Activation Screen Identifies Genes That Protect against Zika Virus Infection.

Zika virus (ZIKV) is an arthropod-borne emerging pathogen causing febrile illness. ZIKV is associated Guillain-Barré syndrome and other neurological complications. Infection during pregnancy is associated with pregnancy complications and developmental and neurological abnormalities collectively defined as congenital Zika syndrome. There is still no vaccine or specific treatment for ZIKV infection. To identify host factors that can rescue cells from ZIKV infection, we used a genome-scale CRISPR activation screen. Our highly ranking hits included a short list of interferon-stimulated genes (ISGs) previously reported to have antiviral activity. Validation of the screen results highlighted interferon lambda 2 (IFN-λ2) and interferon alpha-inducible protein 6 (IFI6) as genes providing high levels of protection from ZIKV. Activation of these genes had an effect on an early stage in viral infection. In addition, infected cells expressing single guide RNAs (sgRNAs) for both of these genes displayed lower levels of cell death than did the controls. Furthermore, the identified genes were significantly induced in ZIKV-infected placenta explants. Thus, these results highlight a set of ISGs directly relevant for rescuing cells from ZIKV infection or its associated cell death and substantiate CRISPR activation screens as a tool to identify host factors impeding pathogen infection.IMPORTANCE Zika virus (ZIKV) is an emerging vector-borne pathogen causing a febrile disease. ZIKV infection might also trigger Guillain-Barré syndrome, neuropathy, and myelitis. Vertical transmission of ZIKV can cause fetus demise, stillbirth, or severe congenital abnormalities and neurological complications. There is no vaccine or specific antiviral treatment against ZIKV. We used a genome-wide CRISPR activation screen, where genes are activated from their native promoters to identify host cell factors that protect cells from ZIKV infection or associated cell death. The results provide a better understanding of key host factors that protect cells from ZIKV infection and might assist in identifying novel antiviral targets.

Transmission of Zika Virus Through the Rectal Route Leads to Mucosal and Systemic Infection with Reduced Neuropathology in Mice

Zika virus (ZIKV) is a mosquito‐borne flavivirus originally confined to Africa and Asia that has most recently spread to the Americas and the Caribbean. ZIKV circulates in sylvatic and urban transmission cycles and causes asymptomatic infection in most affected individuals, while the rest of the population experiences mild febrile syndrome. In some adults, ZIKV causes neurotropic Guillain–Barré syndrome. Vertical transmission of ZIKV in infected mothers causes fetal growth restriction, microcephaly, and congenital eye disease. There have been reports of infected individuals transmitting ZIKV sexually from male to female, male to male, and a suspected case of female to male. ZIKV has been detected in the semen of infected males months after symptom onset and thus, ZIKV persistence in the semen and testes can increase the risk of viral transmission for men having sex with men (MSM) and between heterosexual partners through rectal route. To further understand the risk of ZIKV acquisition through this route, we established a rectal route of infection model using immunocompromised (Ifnar1−/−) mice to investigate the sexual (rectal) and mosquito (subcutaneous) modes of transmission and their resulting systemic and mucosal responses to infection. Rectal inoculation of ZIKV results in viremia with non‐lethal infection, while establishing active rectal and testicular infection that persists for at least 21 days. We found that after one day of infection, ZIKV infects epithelial cells comprising the mucosal epithelium and dendritic cells within the lamina propria and submucosa. Significantly increased levels of the chemokine CCL2 and CD4+ T‐cell response were observed at 3 and 7 days post‐infection, respectively, relative to the subcutaneously infected group. Moreover, rectal route of infection results in reduced immune cell infiltration and inflammation in the brain with a robust CCL2 and CXCl10 response, while subcutaneous infection caused severe brain pathology and induces a more robust CD8+ T‐cell response. Lastly, at 21 days, the rectal group had specific anti‐ZIKV antiviral response suggesting the role of adaptive immune response in restricting lethal viral infection. Our studies provide comprehensive insight of ZIKV transmission through rectal route and the resulting reduced neuropathology and control of disease progression in mice due to early virological and immunological events following infection of the rectal mucosa.Support or Funding InformationThis research was funded by Cedars‐Sinai Medical Center's Institutional Research Award to V.A., the California Institute for Regenerative Medicine (CIRM) Quest – Discovery Stage Research Projects Grant (DISC2‐10188) to V.A. at UCLA, and the UCLA Interdisciplinary Postdoctoral Training Grant (T32) in Virology and Gene Therapy to L.E.M.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Vector Competence of Aedes caspius and Ae. albopictus Mosquitoes for Zika Virus, Spain.

We assessed the vector competence of Aedes caspius and Aedes albopictus mosquitoes in Spain for the transmission of Zika virus. Whereas Ae. albopictus mosquitoes were a competent vector, Ae. caspius mosquitoes were unable to transmit Zika virus. We also identified high levels of vertical transmission of Zika virus in Ae. albopictus mosquitoes.

Quantifying Pregnancy Outcomes in Zika-Infected Women

The perinatal disease burden associated with vertical transmission of Zika virus remains incompletely defined. To assess pregnancy outcomes in women

Cross-Reactive Dengue Virus Antibodies Augment Zika Virus Infection of Human Placental Macrophages

Zika virus (ZIKV), which emerged in regions endemic to dengue virus (DENV), is vertically transmitted and results in adverse pregnancy outcomes. Antibodies to DENV can cross-react with ZIKV, but whether these antibodies influence ZIKV vertical transmission remains unclear. Here, we find that DENV antibodies increase ZIKV infection of placental macrophages (Hofbauer cells [HCs]) from 10% to over 80% and enhance infection of human placental explants. ZIKV-anti-DENV antibody complexes increase viral binding and entry into HCs but also result in blunted type I interferon, pro-inflammatory cytokine, and antiviral responses. Additionally, ZIKV infection of HCs and human placental explants is enhanced in an immunoglobulin G subclass-dependent manner, and targeting FcRn reduces ZIKV replication in human placental explants. Collectively, these findings support a role for pre-existing DENV antibodies in enhancement of ZIKV infection of select placental cell types and indicate that pre-existing immunity to DENV should be considered when addressing ZIKV vertical transmission.

Animal Models of Zika Virus Infection during Pregnancy.

Zika virus (ZIKV) emerged suddenly in the Americas in 2015 and was associated with a widespread outbreak of microcephaly and other severe congenital abnormalities in infants born to mothers infected during pregnancy. Vertical transmission of ZIKV in humans was confirmed when viral RNA was detected in fetal and placental tissues, and this outcome has been recapitulated experimentally in animals. Unlike other flaviviruses, ZIKV is both arthropod- and sexually-transmitted, and has a broad tissue tropism in humans, including multiple tissues of the reproductive tract. The threats posed by ZIKV have prompted the development of multiple in vivo models to better understand the pathogenesis of ZIKV, particularly during pregnancy. Here, we review the progress on animal models of ZIKV infection during pregnancy. These studies have generated a foundation of insights into the biology of ZIKV, and provide a means for evaluating vaccines and therapeutics.

Variations in maternal adenylate cyclase genes are associated with congenital Zika syndrome in a cohort from Northeast, Brazil.

Vertical transmission of Zika virus (ZIKV) is associated with congenital malformations but the mechanism of pathogenesis remains unclear. Although host genetics appear to play a role, no genetic association study has yet been performed to evaluate this question. In order to investigate if maternal genetic variation is associated with Congenital Zika Syndrome (CZS), we conducted a case-control study in a cohort of Brazilian women infected with ZIKV during pregnancy. A total of 100 women who reported symptoms of zika during pregnancy were enrolled and tested for ZIKV. Among 52 women positive for ZIKV infection, 28 were classified as cases and 24 as controls based on the presence or absence of CZS in their infants. Variations in the coding region of 205 candidate genes involved in cAMP signaling or immune response were assessed by high throughput sequencing and tested for association with development of CZS. From the 817 single nucleotide variations (SNVs) included in association analyses, 22 SNVs in 17 genes were associated with CZS under an additive model (alpha=0.05). Variations c.319T>C (rs11676272) and c.1297G>A, located at ADCY3 and ADCY7 genes showed the most prominent effect. The association of ADCY3 and ADCY7 genes was confirmed using a Sequence Kernel Association Test to assess the joint effect of common and rare variations, and results were statistically significant after adjustment for multiple comparisons (P<0.002). These results suggest that maternal ADCY genes contribute to ZIKV pathogenicity and influence the outcome of CZS, being promising candidates for further replication studies and functional analysis.

Evidence of vertical transmission of Zika virus in field-collected eggs of Aedes aegypti in the Brazilian Amazon.

BackgroundArboviruses are viruses transmitted to humans and other animals by the bite of hematophagous arthropods. Infections caused by chikungunya virus (CHIKV), dengue virus (DENV), Zika virus (ZIKV), and the deadlier yellow fever virus (YFV) are current public health problems in several countries, mainly those located in tropical and subtropical regions. One of the main prevention strategies continues to be vector control, with the elimination of breeding sites and surveillance of infested areas. The use of ovitraps for Aedes mosquitos monitoring has already demonstrated promising results, and maybe be also useful for arboviral surveillance.MethodsThis work aimed to detect natural vertical transmission of arboviruses in Aedes aegypti and Aedes albopictus. Mosquito egg collection was carried out using ovitraps in Itacoatiara, a mid-size city in Amazonas state, Brazil. Collected eggs were allowed to hatch and larvae were tested for CHIKV, DENV, and ZIKV RNA by RT-qPCR.ResultsA total of 2,057 specimens (1,793 Ae. aegypti and 264 Ae. albopictus), in 154 larvae pools were processed. Results showed one positive pool for CHIKV and one positive pool for ZIKV. The active ZIKV infection was further confirmed by the detection of the negative-strand viral RNA and nucleotide sequencing which confirmed the Asian genotype. The Infection Rate per 1,000 mosquitoes tested was assessed by Maximum Likelihood Estimation (MLE) with 0.45 and 0.44 for CHIKV and ZIKV, respectively, and by Minimum Infection Rate (MIR) with 0.45 for both viruses.ConclusionTo our knowledge, this is the first detection of ZIKV in natural vertical transmission in the Ae. aegypti, a fact that may contribute to ZIKV maintenance in nature during epidemics periods. Furthermore, our results highlight that the use of ovitraps and the molecular detection of arbovirus may contribute to health surveillance, directing the efforts to more efficient transmission blockade.

Timing of gestational exposure to Zika virus is associated with postnatal growth restriction in a murine model

Vertical transmission of Zika virus leads to infection of neuroprogenitor cells and destruction of brain parenchyma. Recent evidence suggests that the timing of infection as well as host factors may affect vertical transmission. As a result, congenital Zika virus infection may only become clinically apparent in the postnatal period. We sought to develop an outbred mouse model of Zika virus vertical transmission to determine if the timing of gestational Zika virus exposure yields phenotypic differences at birth and through adolescence. We hypothesized that later gestational inoculations would only become apparent in adolescence. To better recapitulate human exposures, timed pregnant Swiss-Webster dams (n= 15) were subcutaneously inoculated with 1× 104 plaque-forming units of first passage contemporary Zika virus HN16 strain or a mock injection on embryonic day 4, 8, or 12 with bioactive antiinterferon alpha receptor antibody administered in days preceding and proceeding inoculation. The antibody was given to prevent the robust type I interferon signaling cascade that make mice inherently resistant to Zika virus infection. At birth and adolescence (6 weeks of age) offspring were assessed for growth, brain weight, and biparietal head diameters, and Zika virus viral levels by reverse transcription-polymerase chain reaction or in situ hybridization. Pups of Zika virus-infected dams infected at embryonic days 4 and 8 but not 12 were growth restricted (P < .003). Brain weights were significantly smaller at birth (P= .01) for embryonic day 8 Zika virus-exposed offspring. At 6 weeks of age, biparietal diameters were smaller for all Zika virus-exposed males and females (P < .05), with embryonic day 8-exposed males smallest by biparietal diameter and growth-restriction measurements (weight >2 SD, P= .0007). All pups and adolescent mice were assessed for Zika virus infection by reverse transcription-polymerase chain reaction. Analysis of all underweight pups reveled 1 to be positive for neuronal Zika virus infection by in situ hybridization, while a second moribund animal was diffusely positive at 8 days of age by Zika virus infectivity throughout the brain, kidneys, and intestine. These findings demonstrate that postnatal effects of infection occurring at single time points continue to be detrimental to offspring in the postnatal period in a subset of littermates and subject to a window of gestational susceptibility coinciding with placentation. This model recapitulates frequently encountered clinical scenarios in nonendemic regions, including the majority of the United States, where travel-related exposure occurs in short and well-defined windows of gestation. Our low rate of infection and relatively rare evidence of congenital Zika syndrome parallels human population-based data.

Blocking Zika virus vertical transmission

The outbreak of the Zika virus (ZIKV) has been associated with increased incidence of congenital malformations. Although recent efforts have focused on vaccine development, treatments for infected individuals are needed urgently. Sofosbuvir (SOF), an FDA-approved nucleotide analog inhibitor of the Hepatitis C (HCV) RNA-dependent RNA polymerase (RdRp) was recently shown to be protective against ZIKV both in vitro and in vivo. Here, we show that SOF protected human neural progenitor cells (NPC) and 3D neurospheres from ZIKV infection-mediated cell death and importantly restored the antiviral immune response in NPCs. In vivo, SOF treatment post-infection (p.i.) decreased viral burden in an immunodeficient mouse model. Finally, we show for the first time that acute SOF treatment of pregnant dams p.i. was well-tolerated and prevented vertical transmission of the virus to the fetus. Taken together, our data confirmed SOF-mediated sparing of human neural cell types from ZIKV-mediated cell death in vitro and reduced viral burden in vivo in animal models of chronic infection and vertical transmission, strengthening the growing body of evidence for SOF anti-ZIKV activity.

Knowledge of Zika and perception of risk among sexually-active adults in the United States of America: results from a nationally representative sample

ABSTRACTObjectiveTo examine knowledge of Zika transmission and risk perception and to assess variability by condom use in a probability sample of sexually-active adults in the United States.MethodsData for this study came from the 2016 wave of the National Survey of Sexual Health and Behavior, a nationally representative probability sample of adults in the United States. Data were collected in November 2016 via a cross-sectional Internet-based survey administered to members of a Knowledge Panel, an address-based random sample service managed by GfK. A weighted subsample (n = 1 713) of sexually active adults, 18 – 50 years of age, was included in analyses.ResultsMore than 90% of men and women reported low or no perceived risk of Zika. Most participants identified mosquito bite as a route of transmission, while significantly fewer identified sexual intercourse (≈ 40%) and vertical (29% men, 41% women) transmission routes.ConclusionSexually-active adults in the United States, especially young men, lack awareness of sexual and vertical transmission of Zika Virus. Given the likely endemic nature of Zika, this low-risk perception is an important prevention challenge. Zika prevention messaging should address lesser known transmission routes, emphasize male education, and promote correct and consistent condom use.

873: Vertical transmission and placental pathology of twin pregnancies from Zika virus infected mothers

Zika virus infection during pregnancy can lead to severe birth defects in the developing fetus. Little is known about the natural history of Zika infection in twin pregnancies. Here, we report on placental pathological findings from twin pregnancies complicated by Zika virus infection in pregnancy, markers of vertical transmission, and concordance. This is a cohort of twin gestations from a prospective study of pregnancies with confirmed maternal Zika virus infection. Timing of Zika infection was confirmed by PCR from maternal samples in Rio de Janeiro, Brazil from 2016 to 2017. Placental specimens were collected at the time of delivery for PCR analysis and pathology. Histopathologic analysis was performed by a placental pathologist. Infants were tested for vertical transmission of Zika virus by PCR at the time of birth. There were three cases of twin gestation with confirmed maternal ZIKV infection in preplacental pathology. All cases were dichorionic/diamniotic twin gestations. Patient characteristics and placental findings are reported in the Table. Patient 1 was infected at 24 weeks gestation; she delivered at 37 weeks. Placental PCR was discordant but both twins were PCR positive. Patient 2 was infected at 33 weeks gestation and delivered at 34 weeks. Both placentas and both twins were PCR positive at birth. Patient 3 was infected at 16 weeks gestation and delivered at 35 weeks. One twin and associated placenta were PCR-positive, while the second twin and placenta were PCR negative. On histopathologic analysis, all six placentas were found to have delayed villous maturation. Placental histopathologic findings were also distinct in each placental pair. Maternal Zika infection in dichorionic-diamniotic twin pregnancies may be discordant in vertical transmision. Placental PCR may be discordant with newborn PCR results. Placentas from each twin may have distinct pathologic findings. These results suggest that each twin should be evaluated individually for Zika infection as ZIKV may not transmit equally to each fetus.

Zika Virus: An Emerging Global Health Threat.

Zika virus (ZIKV) is an emerging healthcare threat. The presence of the mosquito Aedes species across South and Central America in combination with complementary climates have incited an epidemic of locally transmitted cases of ZIKV infection in Brazil. As one of the most significant current public health concerns in the Americas, ZIKV epidemic has been a cause of alarm due to its known and unknown complications. At this point, there has been a clear association between ZIKV infection and severe clinical manifestations in both adults and neonates, including but not limited to neurological deficits such as Guillain-Barré syndrome (GBS) and microcephaly, respectively. The gravity of the fetal anomalies linked to ZIKV vertical transmission from the mother has prompted a discussion on whether to include ZIKV as a formal member of the TORCH [Toxoplasma gondii, other, rubella virus, cytomegalovirus (CMV), and herpes] family of pathogens known to breach placental barriers and cause congenital disease in the fetus. The mechanisms of these complex phenotypes have yet to be fully described. As such, diagnostic tools are limited and no effective modalities are available to treat ZIKV. This article will review the recent advancements in understanding the pathogenesis of ZIKV infection as well as diagnostic tests available to detect the infection. Due to the increase in incidence of ZIKV infections, there is an immediate need to develop new diagnostic tools and novel preventive as well as therapeutic modalities based on understanding the molecular mechanisms underlying the disease.

Organotypic models of type III interferon-mediated protection from Zika virus infections at the maternal–fetal interface

Protecting the fetus from the hematogenous spread of viruses requires multifaceted layers of protection and relies heavily on trophoblasts, the fetal-derived cells that comprise the placental barrier. We showed previously that trophoblasts isolated from full-term placentas resist infection by diverse viruses, including Zika virus (ZIKV), and transfer this resistance to nonplacental cells through the activity of paracrine effectors, including the constitutive release of type III interferons (IFNs). Here, we developed 3D cell-line-based models of human syncytiotrophoblasts, cells that lie in direct contact with maternal blood, and show that these cells recapitulate the antiviral properties of primary trophoblasts through the constitutive release of type III IFNs (IFNλ1 and IFNλ2) and become resistant to ZIKV infection. In addition, using organotypic human midgestation chorionic villous explants, we show that syncytiotrophoblasts isolated from the second trimester of pregnancy also constitutively release type III IFNs and use these IFNs in autocrine and paracrine manners to restrict ZIKV infection. Collectively, these data provide important insights into the defense mechanisms used by syncytiotrophoblasts at various stages of human gestation to resist ZIKV infection and new human models to study the role of type III IFNs in the vertical transmission of ZIKV and other viruses associated with congenital disease.

Sexual and Vertical Transmission of Zika Virus in anti-interferon receptor-treated Rag1-deficient mice

Although Zika virus (ZIKV) is primarily transmitted to humans by the Aedes aegypti mosquito, human-to-human transmission has also been observed from males-to-females as well as mother-to-offspring. In the current study, we studied both sexual transmission (STx) and vertical transmission (VTx) of ZIKV using anti-IFNAR1-treatment of Rag1−/− (AIR) mice. These mice have suppressed type I IFN responses and lack adaptive immune responses, leading to a prolonged infection prior to clinical disease. STx of ZIKV from infected AIR males to naive Ifnar1−/− females was observed with greater than 50% incidence, with infection observed in the vaginal tract at early time points. In the case of a resulting pregnancy, virus was also found in the uterus and placental tissue. In additional studies, VTx of virus was observed in AIR female mice. Specifically, peripheral ZIKV infection of pregnant AIR females resulted in detectable virus in brain and/or lymph nodes of fetuses and/or pups. VTx of ZIKV was stochastic, in that not all fetuses/pups within the same dam had detectable virus and infection was not associated with breakdown of maternal/fetal placental barrier. This provides a new model to study the barriers to STx and VTx of ZIKV and the immune responses essential to preventing transmission.

Inhibition of autophagy limits vertical transmission of Zika virus in pregnant mice.

Zika virus (ZIKV) infection during pregnancy leads to devastating fetal outcomes, including intrauterine growth restriction and microcephaly. Greater understanding of mechanisms underlying ZIKV maternal-fetal transmission is needed to develop new therapeutic interventions. Here, we define an important role for the autophagy pathway in ZIKV vertical transmission. ZIKV infection induced autophagic activity in human trophoblasts and pharmacological inhibition limited ZIKV infectivity. Furthermore, deficiency in an essential autophagy gene, Atg16l1, in mice limited ZIKV vertical transmission and placental and fetal damage and overall improved placental and fetal outcomes. This protection was due to a placental trophoblast cell-autonomous effect of autophagic activity, not to alterations in systemic maternal ZIKV infection. Finally, an autophagy inhibitor, hydroxychloroquine, approved for use in pregnant women, attenuated placental and fetal ZIKV infection and ameliorated adverse placental and fetal outcomes. Our study reveals new insights into the mechanism of ZIKV vertical transmission and suggests that an autophagy-based therapeutic warrants possible evaluation in humans to diminish the risks of ZIKV maternal-fetal transmission.

Congenital Zika virus infection: More than just microcephaly.

A nonhuman primate model demonstrates efficient vertical transmission of Zika virus.

Mathematical model of Zika virus with vertical transmission.

Zika is a flavivirus transmitted to humans through either the bites of infected Aedes mosquitoes or sexual transmission. Zika has been linked to congenital anomalies such as microcephaly. In this paper, we analyze a new system of ordinary differential equations which incorporates human vertical transmission of Zika virus, the birth of babies with microcephaly and asymptomatically infected individuals. The Zika model is locally and globally asymptotically stable when the basic reproduction number is less than unity. Our model shows that asymptomatic individuals amplify the disease burden in the community, and the most important parameters for ZIKV spread are the death rate of mosquitoes, the mosquito biting rate, the mosquito recruitment rate, and the transmission per contact to mosquitoes and to adult humans. Scenario exploration indicates that personal-protection is a more effective control strategy than mosquito-reduction strategy. It also shows that delaying conception reduces the number of microcephaly cases, although this does little to prevent Zika transmission in the broader community. However, by coupling aggressive vector control and personal protection use, it is possible to reduce both microcephaly and Zika transmission. 2000 Mathematics Subject Classifications: 92B05, 93A30, 93C15.

Zika virus: Future reproductive concerns.

The pandemic spread of Zika virus (ZIKV), a member of the flavivirus genus of the Flaviviridae family, has become a major public health concern. Reproductive specialists are particularly concerned over the spread of ZIKV as it is now known to have both sexual and transplacental routes of transmission resulting in fetal congenital abnormalities. Other members of the Flaviviridae family, hepatitis C virus (HCV) and bovine viral diarrhea virus (BVDV) (which primarily affects cattle), are well known to reproductive specialists as both sexually transmitted illnesses that are capable of vertical transmission. Congenital infection with BVDV also has a predilection for neuro-teratogenicity as has been seen with ZIKV. HCV and BVDV are also known to be capable of persistent infection in offspring. Could this be the case with ZIKV? Examining what we know about HCV and BVDV, in addition to what we have already learned about ZIKV, may answer some of the questions that remain about ZIKV. Herein, we review the current literature as it pertains to ZIKV vertical transmission and neuro-teratogenicity and compare it to what is known about HCV and BVDV.