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heterologous protection against asian zika virus challenge in rhesus macaques.zika virus (zikv; flaviviridae, flavivirus) was declared a public health emergency of international concern by the world health organization (who) in february 2016, because of the evidence linking infection with zikv to neurological complications, such as guillain-barre syndrome in adults and congenital birth defects including microcephaly in the developing fetus. because development of a zikv vaccine is a top research priority and because the genetic and antigenic variability of many rna viruse ...201627911897
a rhesus macaque model of asian-lineage zika virus infection.infection with asian-lineage zika virus (zikv) has been associated with guillain-barré syndrome and fetal abnormalities, but the underlying mechanisms remain poorly understood. animal models of infection are thus urgently needed. here we show that rhesus macaques are susceptible to infection by an asian-lineage zikv closely related to strains currently circulating in the americas. following subcutaneous inoculation, zikv rna is detected in plasma 1 day post infection (d.p.i.) in all animals (n=8 ...201627352279
development of a zika virus infection model in cynomolgus macaques.limited availability of indian rhesus macaques (irm) is a bottleneck to study zika virus (zikv) pathogenesis and evaluation of appropriate control measures in non-human primates. to address these issues, we report here the mauritian cynomolgus macaque (mcm) model for zikv infection. in brief, six mcms (seronegative for dengue and zikv) were subdivided into three cohorts with a male and female each and challenged with different doses of asian [prvabc59 (puerto rico) or fss13025 (cambodia)] or afr ...201628066354
the brazilian zika virus strain causes birth defects in experimental models.zika virus (zikv) is an arbovirus belonging to the genus flavivirus (family flaviviridae) and was first described in 1947 in uganda following blood analyses of sentinel rhesus monkeys. until the twentieth century, the african and asian lineages of the virus did not cause meaningful infections in humans. however, in 2007, vectored by aedes aegypti mosquitoes, zikv caused the first noteworthy epidemic on the yap island in micronesia. patients experienced fever, skin rash, arthralgia and conjunctiv ...027279226
the zika outbreak of the 21st century.the zika virus outbreak has captivated the attention of the global audience and information has spread rapidly and wildly through the internet and other media channels. this virus was first identified in 1947, when it was isolated from a sentinel rhesus monkey placed by british scientists working at the yellow fever research laboratory located in the zika forest area of uganda, hence its name, and is transmitted primarily by the mosquito vector, aedes aegypti. the fact that the rhesus macaque is ...201626925496
[zika virus: a review to clinicians].zika virus is a flavivirus related to dengue virus, yellow fever virus and west nile virus. it is considered an emerging arbovirus transmitted by mosquitos of the genus aedes. its first description took place in 1947 in the zika forest in uganda, isolated on rhesus monkey used as bait to study the yellow fever virus. sporadic cases have been detected in african countries and at the end of the 70's in indonesia. in 2007, epidemics were described in micronesia and other islands in the pacific ocea ...201626849762
zika virus tissue and blood compartmentalization in acute infection of rhesus macaques.animal models of zika virus (zikv) are needed to better understand tropism and pathogenesis and to test candidate vaccines and therapies to curtail the pandemic. humans and rhesus macaques possess similar fetal development and placental biology that is not shared between humans and rodents. we inoculated 2 non-pregnant rhesus macaques with a 2015 brazilian zikv strain. consistent with most human infections, the animals experienced no clinical disease but developed short-lived plasma viremias tha ...201728141843
zika virus: a new threat to human reproduction.zika virus (zikv) was first isolated in 1947 in a rhesus monkey from the zika forest of uganda. until 2007, only 14 human cases were reported. the first large human outbreak occurred in 2007 (yap island, federated states of micronesia, pacific) followed by french polynesia in 2013 and brazil in 2015. the virus is mainly transmitted through aedes mosquito bites, but sexual and post-transfusion transmissions have been reported. symptoms include low-grade fever, maculopapular rash, conjunctivitis, ...201727966802
zika virus in asia.zika virus (zikv) is an emerging mosquito-borne virus that was first isolated from a sentinel rhesus monkey in the zika forest in uganda in 1947. in asia, the virus was isolated in malaysia from aedes aegypti mosquitoes in 1966, and the first human infections were reported in 1977 in central java, indonesia. in this review, all reported cases of zikv infection in asia as of september 1, 2016 are summarized and some of the hypotheses that could currently explain the apparently low incidence of zi ...201727939768
understanding zika virus.this article describes what pediatric healthcare professionals should know about zika virus (zikv).201727862959
protective efficacy of multiple vaccine platforms against zika virus challenge in rhesus monkeys.zika virus (zikv) is responsible for a major ongoing epidemic in the americas and has been causally associated with fetal microcephaly. the development of a safe and effective zikv vaccine is therefore an urgent global health priority. here we demonstrate that three different vaccine platforms protect against zikv challenge in rhesus monkeys. a purified inactivated virus vaccine induced zikv-specific neutralizing antibodies and completely protected monkeys against zikv strains from both brazil a ...201627492477
zika virus: history of a newly emerging arbovirus.zika virus was originally identified in a sentinel rhesus monkey in the zika forest of uganda in 1947. the virus is a member of the family flaviviridae, genus flavivirus, and is transmitted to humans by aedes species mosquitoes. the first report of zika virus outside africa and asia was in 2007 when the virus was associated with a small outbreak in yap state, part of the federated states of micronesia. since then, zika virus infections have been reported around the world, including in southeast ...201627282424
zika virus update ii: recent development of animal models-proofs of association with human pathogenesis.three recent studies in pregnant mice and one ongoing study in rhesus macaques evaluating the effect of zikv infection have provided important information about maternal-fetus transmission and zikv-related pathogenesis, confirming a causal role of zikv in neurological problems observed in humans. here, we present an update of these works published in the past few weeks. j. med. virol. 88:1657-1658, 2016. © 2016 wiley periodicals, inc.201627208545
zika virus: yet another emerging threat to nepal.zika virus (zikv) is a flavivirus with single stranded rna related to yellow fever, dengue, west nile, and japanese encephalitis viruses and is transmitted by aedes mosquitoes primarily by aedes aegipti which is widely distributed in nepal. zikv was first identified incidentally in rhesus monkey in uganda in 1947 and human infection in 1952; and by now outbreaks of zikv disease have been recorded in africa, the americas, asia and the pacific. the world health organization (who) has recently decl ...201627005721
the convergence of a virus, mosquitoes, and human travel in globalizing the zika epidemic.the zika virus was first identified in 1947 in the zika forest of uganda. it was discovered in a rhesus monkey that had been placed in a cage on a sentinel platform in the forest by the virus research institute. when this writer visited the institute and the zika forest in 1961, work was underway to identify mosquito species at various levels of the tree canopy. this was done through the placement of traps at various levels of a 120-foot-high steel tower which this writer climbed. at that time, ...201626969497
high infection rates for adult macaques after intravaginal or intrarectal inoculation with zika virus.unprotected sexual intercourse between persons residing in or traveling from regions with zika virus transmission is a risk factor for infection. to model risk for infection after sexual intercourse, we inoculated rhesus and cynomolgus macaques with zika virus by intravaginal or intrarectal routes. in macaques inoculated intravaginally, we detected viremia and virus rna in 50% of macaques, followed by seroconversion. in macaques inoculated intrarectally, we detected viremia, virus rna, or both, ...201728548637
a new threat to human reproduction system posed by zika virus (zikv): from clinical investigations to experimental studies.zika virus (zikv) was first isolated in 1947 from a rhesus monkey in the zika forest of uganda. zikv has since been silently circulating in a number of equatorial countries for over 50 years. the largest outbreak in humans occurred in brazil in 2015-2016. unlike its flavivirus relatives, sexual and post-transfusion transmissions of zikv have been reported. in addition, fetal infection can result in microcephaly and congenital zikv syndrome has been reported in neonates. moreover, zikv rna can pe ...201728893652
prior exposure to zika virus significantly enhances peak dengue-2 viremia in rhesus macaques.structural and functional homologies between the zika and dengue viruses' envelope proteins raise the possibility that cross-reactive antibodies induced following zika virus infection might enhance subsequent dengue infection. using the rhesus macaque model we show that prior infection with zika virus leads to a significant enhancement of dengue-2 viremia that is accompanied by neutropenia, lympocytosis, hyperglycemia, and higher reticulocyte counts, along with the activation of pro-inflammatory ...201728874759
impact of prior flavivirus immunity on zika virus infection in rhesus macaques.studies have demonstrated cross-reactivity of anti-dengue virus (denv) antibodies in human sera against zika virus (zikv), promoting increased zikv infection in vitro. however, the correlation between in vitro and in vivo findings is not well characterized. thus, we evaluated the impact of heterotypic flavivirus immunity on zikv titers in biofluids of rhesus macaques. animals previously infected (≥420 days) with denv2, denv4, or yellow fever virus were compared to flavivirus-naïve animals follow ...201728771605
oropharyngeal mucosal transmission of zika virus in rhesus macaques.zika virus is present in urine, saliva, tears, and breast milk, but the transmission risk associated with these body fluids is currently unknown. here we evaluate the risk of zika virus transmission through mucosal contact in rhesus macaques. application of high-dose zika virus directly to the tonsils of three rhesus macaques results in detectable plasma viremia in all animals by 2 days post-exposure; virus replication kinetics are similar to those observed in animals infected subcutaneously. th ...201728765581
macaque monkeys in zika virus research: 1947-present.zika virus was first isolated in 1947 from an exotic rhesus macaque. nearly 70 years later, the emergence of zika virus in the americas and its newly described association with birth defects has motivated the development of captive macaque monkey models of human zika virus infection. this review describes similarities between macaque and human zika virus pathogenesis and discusses specific advantages and disadvantages of using macaques instead of other laboratory animal models. in particular, ma ...201728750247
zika virus preferentially replicates in the female reproductive tract after vaginal inoculation of rhesus macaques.zika virus (zikv) is a mosquito-transmitted virus that can cause severe defects in an infected fetus. zikv is also transmitted by sexual contact, although the relative importance of sexual transmission is unclear. to better understand the role of sexual transmission in zikv pathogenesis, a nonhuman primate (nhp) model of vaginal transmission was developed. zikv was readily transmitted to mature cycling female rhesus macaque (rm) by vaginal inoculation with 104-106 plaque-forming units (pfu). how ...201728746373
immune cell dynamics in rhesus macaques infected with a brazilian strain of zika virus.zika virus (zikv) is a mosquito-borne and sexually transmitted flavivirus that is associated with fetal cns-damaging malformations during pregnancy in humans. this study documents the viral kinetics and immune responses in rhesus macaques infected with a clinical zikv brazilian isolate. we evaluated the viral kinetics and immune responses induced after an i.v. infection with a brazilian zikv clinical isolate (hs-2015-ba-01) in rhesus macaques for up to 142 d. zikv-specific ab-secreting cells, ge ...201728667164
zika virus pathogenesis in rhesus macaques is unaffected by pre-existing immunity to dengue virus.zika virus (zikv) is a re-emerging virus that has recently spread into dengue virus (denv) endemic regions and cross-reactive antibodies (abs) could potentially affect zikv pathogenesis. using denv-immune serum, it has been shown in vitro that antibody-dependent enhancement (ade) of zikv infection can occur. here we study the effects of pre-existing denv immunity on zikv infection in vivo. we infect two cohorts of rhesus macaques with zikv; one cohort has been exposed to denv 2.8 years earlier a ...201728643775
highly efficient maternal-fetal zika virus transmission in pregnant rhesus macaques.infection with zika virus (zikv) is associated with human congenital fetal anomalies. to model fetal outcomes in nonhuman primates, we administered asian-lineage zikv subcutaneously to four pregnant rhesus macaques. while non-pregnant animals in a previous study contemporary with the current report clear viremia within 10-12 days, maternal viremia was prolonged in 3 of 4 pregnancies. fetal head growth velocity in the last month of gestation determined by ultrasound assessment of head circumferen ...201728542585
emerging zika virus disease: a public health emergency of global concern.infectious diseases remain a leading source of human morbidity and mortality. recently, emerging infectious diseases are dominated by zoonoses, and eventually rising considerably. their emergence is dependent on various factors especially, socioeconomic, environmental and ecological factors etc. recently, the swift spread of zika virus (zikv) through the americas, simultaneously with the association of infection with microcephaly and guillain-barré syndrome, has strained this previously overlook ...201628466030
zika virus persistence in the central nervous system and lymph nodes of rhesus monkeys.zika virus (zikv) is associated with severe neuropathology in neonates as well as guillain-barré syndrome and other neurologic disorders in adults. prolonged viral shedding has been reported in semen, suggesting the presence of anatomic viral reservoirs. here we show that zikv can persist in cerebrospinal fluid (csf) and lymph nodes (ln) of infected rhesus monkeys for weeks after virus has been cleared from peripheral blood, urine, and mucosal secretions. zikv-specific neutralizing antibodies co ...201728457610
a single-dose live-attenuated vaccine prevents zika virus pregnancy transmission and testis damage.zika virus infection during pregnancy can cause congenital abnormities or fetal demise. the persistence of zika virus in the male reproductive system poses a risk of sexual transmission. here we demonstrate that live-attenuated zika virus vaccine candidates containing deletions in the 3' untranslated region of the zika virus genome (zikv-3'utr-lav) prevent viral transmission during pregnancy and testis damage in mice, as well as infection of nonhuman primates. after a single-dose vaccination, pr ...201728939807
development of a chimeric zika vaccine using a licensed live-attenuated flavivirus vaccine as backbone.the global spread of zika virus (zikv) and its unexpected association with congenital defects necessitates the rapid development of a safe and effective vaccine. here we report the development and characterization of a recombinant chimeric zikv vaccine candidate (termed chinzikv) that expresses the prm-e proteins of zikv using the licensed japanese encephalitis live-attenuated vaccine sa14-14-2 as the genetic backbone. chinzikv retains its replication activity and genetic stability in vitro, whi ...201829445153
ocular and uteroplacental pathology in a macaque pregnancy with congenital zika virus infection.congenital zika virus (zikv) infection impacts fetal development and pregnancy outcomes. we infected a pregnant rhesus macaque with a puerto rican zikv isolate in the first trimester. the pregnancy was complicated by preterm premature rupture of membranes (pprom), intraamniotic bacterial infection and fetal demise 49 days post infection (gestational day 95). significant pathology at the maternal-fetal interface included acute chorioamnionitis, placental infarcts, and leukocytoclastic vasculitis ...201829381706
zika virus infection in pregnant rhesus macaques causes placental dysfunction and immunopathology.zika virus (zikv) infection during pregnancy leads to an increased risk of fetal growth restriction and fetal central nervous system malformations, which are outcomes broadly referred to as the congenital zika syndrome (czs). here we infect pregnant rhesus macaques and investigate the impact of persistent zikv infection on uteroplacental pathology, blood flow, and fetal growth and development. despite seemingly normal fetal growth and persistent fetal-placenta-maternal infection, advanced non-in ...201829343712
durability and correlates of vaccine protection against zika virus in rhesus monkeys.an effective zika virus (zikv) vaccine will require long-term durable protection. several zikv vaccine candidates have demonstrated protective efficacy in nonhuman primates, but these studies have typically involved zikv challenge shortly after vaccination at peak immunity. we show that a single immunization with an adenovirus vector-based vaccine, as well as two immunizations with a purified inactivated virus vaccine, afforded robust protection against zikv challenge in rhesus monkeys at 1 year ...201729237759
infection via mosquito bite alters zika virus tissue tropism and replication kinetics in rhesus macaques.mouse and nonhuman primate models now serve as useful platforms to study zika virus (zikv) pathogenesis, candidate therapies, and vaccines, but they rely on needle inoculation of virus: the effects of mosquito-borne infection on disease outcome have not been explored in these models. here we show that infection via mosquito bite delays zikv replication to peak viral loads in rhesus macaques. importantly, in mosquito-infected animals zikv tissue distribution was limited to hemolymphatic tissues, ...201729235456
fetal neuropathology in zika virus-infected pregnant female rhesus monkeys.the development of interventions to prevent congenital zika syndrome (czs) has been limited by the lack of an established nonhuman primate model. here we show that infection of female rhesus monkeys early in pregnancy with zika virus (zikv) recapitulates many features of czs in humans. we infected 9 pregnant monkeys with zikv, 6 early in pregnancy (weeks 6-7 of gestation) and 3 later in pregnancy (weeks 12-14 of gestation), and compared findings with uninfected controls. 100% (6 of 6) of monkeys ...201829606355
zika virus disease.the zika virus is an arbovirus belonging to the virus family flaviviridae. the virus was isolated in 1947 from a rhesus monkey in the zika forest of uganda. the virus causes sporadic mild human infections in africa and later in asia. however, by 2007 a major shift in its infection pattern was noticed and thousands of human infections were reported in the state of yap and federated states of micronesia. in the last 3 years, major outbreaks have continued to occur and the virus has spread to sever ...201930787745
translational model of zika virus disease in baboons.zika virus (zikv) is an emerging mosquito-borne flavivirus with devastating outcomes seen recently in the americas due to the association of maternal zikv infection with fetal microcephaly and other fetal malformations not previously associated with flavivirus infections. here, we have developed the olive baboon (papio anubis) as a nonhuman primate (nhp) translational model for the study of zikv pathogenesis and associated disease outcomes to contrast and compare with humans and other major nhps ...201829875247
a simple flow cytometry based assay to determine in vitro antibody dependent enhancement of dengue virus using zika virus convalescent serum.antibody dependent enhancement of infection has been shown to play a major role in dengue viral pathogenesis. traditional assays that measure the capacity of antibodies or serum to enhance infection in impermissible cell lines have relied on using viral output in the media followed by plaque assays to quantify infection. more recently, these assays have examined dengue virus (denv) infection in the cell lines using fluorescently labeled antibodies. both these approaches have limitations that res ...201829708542
embryotoxic impact of zika virus in a rhesus macaque in vitro implantation model.zika virus infection (zikv) is associated with adverse pregnancy outcomes in humans, and infection in the first trimester can lead to miscarriage and stillbirth. vertical and sexual transmission of zikv have been demonstrated, yet the impact of infection during the initial stages of pregnancy remains unexplored. here we defined the impact of zikv on early embryonic and placental development with a rhesus macaque model. during in vitro fertilization (ivf), macaque gametes were inoculated with a p ...202031901091
correction: zika virus infection of rhesus macaques leads to viral persistence in multiple tissues.[this corrects the article doi: 10.1371/journal.ppat.1006219.].201728380070
evolving rna virus pandemics: hiv, hcv, ebola, dengue, chikunguya, and now zika!the zika virus (zikv), a flavivirus related to yellow fever, dengue, and west nile, originated in the zika forest in uganda and was discovered in a rhesus monkey in 1947. the disease now has "explosive" pandemic potential, with outbreaks in africa, southeast asia, the pacific islands, and the americas. to date, the cdc has issued travel alerts for at least 30 countries and territories in latin america, the caribbean, polynesia, and cape verde in africa.201627028271
characterization of a 2016 clinical isolate of zika virus in non-human primates.animal models are critical to understand disease and to develop countermeasures for the ongoing epidemics of zika virus (zikv). here we report a non-human primate model using a 2016 contemporary clinical isolate of zikv. upon subcutaneous inoculation, rhesus macaques developed fever and viremia, with robust excretion of zikv rna in urine, saliva, and lacrimal fluid. necropsy of two infected animals revealed that systematic infections involving central nervous system and visceral organs were esta ...201627693104
zika virus infection of rhesus macaques leads to viral persistence in multiple tissues.zika virus (zikv), an emerging flavivirus, has recently spread explosively through the western hemisphere. in addition to symptoms including fever, rash, arthralgia, and conjunctivitis, zikv infection of pregnant women can cause microcephaly and other developmental abnormalities in the fetus. we report herein the results of zikv infection of adult rhesus macaques. following subcutaneous infection, animals developed transient plasma viremia and viruria from 1-7 days post infection (dpi) that was ...201728278237
25-hydroxycholesterol protects host against zika virus infection and its associated microcephaly in a mouse model.zika virus (zikv) has become a public health threat due to its global transmission and link to severe congenital disorders. the host immune responses to zikv infection have not been fully elucidated, and effective therapeutics are not currently available. herein, we demonstrated that cholesterol-25-hydroxylase (ch25h) was induced in response to zikv infection and that its enzymatic product, 25-hydroxycholesterol (25hc), was a critical mediator of host protection against zikv. synthetic 25hc addi ...201728314593
dna vaccination before conception protects zika virus-exposed pregnant macaques against prolonged viremia and improves fetal outcomes.zika virus (zikv) infection of pregnant women is associated with congenital zika syndrome (czs) and no vaccine is available, although several are being tested in clinical trials. we tested the efficacy of zikv dna vaccine vrc5283 in a rhesus macaque model of congenital zikv infection. most animal vaccine experiments have a set pathogen exposure several weeks or months after vaccination. in the real world, people encounter pathogens years or decades after vaccination, or may be repeatedly exposed ...201931852797
long-term protection of rhesus macaques from zika virus reinfection.by the end of the 2016 zika virus (zikv) outbreak, it is estimated that there were up to 100 million infections in the americas. in approximately one in seven infants born to mothers infected during pregnancy, zikv has been linked to microcephaly, developmental delays, or other congenital disorders collectively known as congenital zika syndrome (czs) as well as guillain-barré syndrome (gbs) in zikv infected adults. it is a global health priority to develop a vaccine against zikv that elicits lon ...201931801867
simian immunodeficiency virus infection of rhesus macaques results in delayed zika virus clearance.flaviviruses are controlled by adaptive immune responses but are exquisitely sensitive to interferon-stimulated genes (isgs). how coinfections, particularly simian immunodeficiency viruses (sivs), that induce robust isg signatures influence flavivirus clearance and pathogenesis is unclear. here, we studied how zika virus (zikv) infection is modulated in siv-infected nonhuman primates. we measured zikv replication, cellular zikv rna levels, and immune responses in non-siv-infected and siv-infecte ...201931796542
zika virus causes acute and chronic prostatitis in mice and macaques.sexual transmission and persistence of zika virus (zikv) in the male reproductive tract has raised concerned for potential damaging effects on function. animal studies have demonstrated that zikv virus can infect and damage the testis and epididymis, and these results has been correlated to lower sperm counts in zikv-infected humans. the prostate plays a vital role in the male reproductive tract, with acute and chronic prostatitis linked to male infertility. here, we evaluated the effects of zik ...201931616920
high susceptibility, viral dynamics and persistence of south american zika virus in new world monkey species.south american zika virus (zikv) recently emerged as a novel human pathogen, linked with neurological disorders. however, comparative zikv infectivity studies in new world primates are lacking. two members of the callitrichidae family, common marmosets (callithrix jacchus) and red-bellied tamarins (saguinus labiatus), were highly susceptible to sub-cutaneous challenge with the puerto rico-origin zikvprvabc59 strain. both exhibited rapid, high, acute viraemia with early neuroinvasion (3 days) in ...201931601848
cell death and zika virus: an integrated network of the mechanisms of cell injury.zika virus (zikv) is an arbovirus that is transmitted by aedes mosquitos. its prototype was isolated in 1947 from serum of a sentinel rhesus monkey (macaca mulatta) in the zika forest of uganda. as a member of the genus flavivirus, family flaviviridae, zikv is enveloped and icosahedral and possesses a single-stranded, positive-sense rna genome of approximately 10.7 kb. epidemiologically, infection by zikv has become a global health concern in recent years because of the occurrence of epidemics, ...201931571944
time elapsed between zika and dengue virus infections affects antibody and t cell responses.zika virus (zikv) and dengue virus (denv) are co-endemic in many parts of the world, but the impact of zikv infection on subsequent denv infection is not well understood. here we show in rhesus macaques that the time elapsed after zikv infection affects the immune response to denv infection. we show that previous zikv exposure increases the magnitude of the antibody and t cell responses against denv. the time interval between zikv and subsequent denv infection further affects the immune response ...201931541110
extensive genomic recoding by codon-pair deoptimization selective for mammals is a flexible tool to generate attenuated vaccine candidates for dengue virus 2.the four serotypes of dengue virus (denv) are the leading etiologic agent of disease caused by arthropod-borne viruses (arboviruses) in the world, with billions at risk of denv infection spread by infected mosquitoes. denv causes illness ranging from dengue fever (df) to life-threatening dengue hemorrhagic fever (dhf) and dengue shock syndrome (dss). denv proliferates well in two different host systems, an invertebrate mosquito vector and vertebrate primate host, which have a distinct difference ...201931539771
postnatal zika virus infection of nonhuman primate infants born to mothers infected with homologous brazilian zika virus.recent data in a nonhuman primate model showed that infants postnatally infected with zika virus (zikv) were acutely susceptible to high viremia and neurological damage, suggesting the window of vulnerability extends beyond gestation. in this pilot study, we addressed the susceptibility of two infant rhesus macaques born healthy to dams infected with zika virus during pregnancy. passively acquired neutralizing antibody titers dropped below detection limits between 2 and 3 months of age, while bi ...201931488856
primary infection with dengue or zika virus does not affect the severity of heterologous secondary infection in macaques.zika virus (zikv) and dengue virus (denv) are genetically and antigenically related flaviviruses that now co-circulate in much of the tropical and subtropical world. the rapid emergence of zikv in the americas in 2015 and 2016, and its recent associations with guillain-barré syndrome, birth defects, and fetal loss have led to the hypothesis that denv infection induces cross-reactive antibodies that influence the severity of secondary zikv infections. it has also been proposed that pre-existing z ...201931369649
high-throughput screening identifies mixed-lineage kinase 3 as a key host regulatory factor in zika virus infection.the zika virus (zikv) life cycle involves multiple steps and requires interactions with host factors. however, the inability to systematically identify host regulatory factors for zikv has hampered antiviral development and our understanding of pathogenicity. here, using a bioactive compound library with 2,659 small molecules, we applied a high-throughput and imaging-based screen to identify host factors that modulate zikv infection. the screen yielded hundreds of hits that markedly inhibited or ...201931270223
using macaques to address critical questions in zika virus research.zika virus (zikv) and nonhuman primates have been inextricably linked since the virus was first discovered in a sentinel rhesus macaque in uganda in 1947. soon after zikv was epidemiologically associated with birth defects in brazil late in 2015, researchers capitalized on the fact that rhesus macaques are commonly used to model viral immunity and pathogenesis, quickly establishing macaque models for zikv infection. within months, the susceptibility of pregnant macaques to experimental zikv chal ...201931180813
zika virus infection induces elevation of tissue factor production and apoptosis on human umbilical vein endothelial cells.zika virus (zikv) infection is typically characterized by a mild disease presenting with fever, maculopapular rash, headache, fatigue, myalgia, and arthralgia. a recent animal study found that zikv-infected pregnant ifnar-/-mice developed vascular damage in the placenta and reduced amount of fetal capillaries. moreover, zikv infection causes segmental thrombosis in the umbilical cord of pregnant rhesus macaques. furthermore, several case reports suggest that zikv infection cause coagulation diso ...201931068911
in vivo delivery of a dna-encoded monoclonal antibody protects non-human primates against zika virus.zika virus (zikv) infection is endemic to several world regions, and many others are at high risk for seasonal outbreaks. synthetic dna-encoded monoclonal antibody (dmab) is an approach that enables in vivo delivery of highly potent mabs to control infections. we engineered dmab-zk190, encoding the mab zk190 neutralizing antibody, which targets the zikv e protein diii domain. in vivo-delivered dmab-zk190 achieved expression levels persisting >10 weeks in mice and >3 weeks in non-human primate (n ...201930962164
zika virus in peridomestic neotropical primates, northeast brazil.zika virus (zikv) is a mosquito-borne viral disease associated with fetal microcephaly and other central nervous system (cns) symptomatology. it was first identified in a rhesus macaque in uganda in 1947 and later in humans (zika fever). in 2015, zikv was notified in northeast brazil where it was associated with cns alterations and with rapid epidemic spread. considering that zikv infects old world monkeys, the aim of this study was to follow its potential in neotropical primates. here, we show ...201930690661
does prior dengue virus exposure worsen clinical outcomes of zika virus infection? a systematic review, pooled analysis and lessons learned.zika virus (zikv) recently caused a pandemic complicated by guillain-barre syndrome (gbs) and birth defects. zikv is structurally similar to the dengue viruses (denv) and in vitro studies suggest antibody dependent enhancement occurs in zikv infections preceded by denv; however, the clinical significance of this remains unclear. we undertook a prisma-adherent systematic review of all current human and non-human primate (nhp) data to determine if prior infection with denv, compared to denv-naïve ...201930682026
siv/shiv-zika co-infection does not alter disease pathogenesis in adult non-pregnant rhesus macaque model.due to the large geographical overlap of populations exposed to zika virus (zikv) and human immunodeficiency virus (hiv), understanding the disease pathogenesis of co-infection is urgently needed. this warrants the development of an animal model for hiv-zikv co-infection. in this study, we used adult non-pregnant macaques that were chronically infected with simian immunodeficiency virus/chimeric simian human immunodeficiency virus (siv/shiv) and then inoculated with zikv. plasma viral loads of b ...201830359380
preliminary studies on immune response and viral pathogenesis of zika virus in rhesus macaques.zika virus (zikv) is primarily transmitted through mosquito bites. it can also be transmitted during sexual intercourse and in utero from mother to fetus. to gain preliminary insight into zikv pathology and immune responses on route of transmission, rhesus macaques (rms) were inoculated with zikv (prvabc59) via intravaginal (ivag) (n = 3) or subcutaneous (sub q) (n = 2) routes. systemic zikv infection was observed in all rms, regardless of the route of inoculation. after 9 days postinfection (dp ...201830127237
erratum for the research article: "durability and correlates of vaccine protection against zika virus in rhesus monkeys" by p. abbink, r. a. larocca, k. visitsunthorn, m. boyd, r. a. de la barrera, g. d. gromowski, m. kirilova, r. peterson, z. li, o. nanayakkara, r. nityanandam, n. b. mercado, e. n. borducchi, a. chandrashekar, d. jetton, s. mojta, p. gandhi, j. lesuer, s. khatiwada, m. g. lewis, k. modjarrad, r. g. jarman, k. h. eckels, s. j. thomas, n. l. michael, d. h. barouch. 201830021887
intraamniotic zika virus inoculation of pregnant rhesus macaques produces fetal neurologic disease.zika virus (zikv) infection of pregnant women can cause fetal microcephaly and other neurologic defects. we describe the development of a non-human primate model to better understand fetal pathogenesis. to reliably induce fetal infection at defined times, four pregnant rhesus macaques are inoculated intravenously and intraamniotically with zikv at gestational day (gd) 41, 50, 64, or 90, corresponding to first and second trimester of gestation. the gd41-inoculated animal, experiencing fetal death ...201829925843
therapeutic and protective efficacy of a dengue antibody against zika infection in rhesus monkeys.strategies to treat zika virus (zikv) infection in dengue virus (denv)-endemic areas are urgently needed. here we show that a denv-specific antibody against the e-dimer epitope (ede) potently cross-neutralizes zikv and provides robust therapeutic efficacy as well as prophylactic efficacy against zikv in rhesus monkeys. viral escape was not detected, suggesting a relatively high bar to escape. these data demonstrate the potential for antibody-based therapy and prevention of zikv.201829867228
comparative pathogenesis of asian and african-lineage zika virus in indian rhesus macaque's and development of a non-human primate model suitable for the evaluation of new drugs and vaccines.the establishment of a well characterized non-human primate model of zika virus (zikv) infection is critical for the development of medical interventions. in this study, challenging indian rhesus macaques (irms) with zikv strains of the asian lineage resulted in dose-dependent peak viral loads between days 2 and 5 post infection and a robust immune response which protected the animals from homologous and heterologous re-challenge. in contrast, viremia in irms challenged with an african lineage s ...201829723973
fetal demise and failed antibody therapy during zika virus infection of pregnant macaques.zika virus (zikv) infection of pregnant women is associated with pathologic complications of fetal development. here, we infect pregnant rhesus macaques (macaca mulatta) with a minimally passaged zikv isolate from rio de janeiro, where a high rate of fetal development complications was observed. the infection of pregnant macaques with this virus results in maternal viremia, virus crossing into the amniotic fluid (af), and in utero fetal deaths. we also treated three additional zikv-infected preg ...201829691387
postnatal zika virus infection is associated with persistent abnormalities in brain structure, function, and behavior in infant macaques.the zika virus (zikv) epidemic is associated with fetal brain lesions and other serious birth defects classified as congenital zikv syndrome. postnatal zikv infection in infants and children has been reported; however, data on brain anatomy, function, and behavioral outcomes following infection are absent. we show that postnatal zikv infection of infant rhesus macaques (rms) results in persistent structural and functional alterations of the central nervous system compared to age-matched controls ...201829618564
immune outcomes of zika virus infection in nonhuman primates.although the zika virus (zikv) epidemic is subsiding, immune responses that are important for controlling acute infection have not been definitively characterized. nonhuman primate (nhp) models were rapidly developed to understand the disease and to test vaccines, and these models have since provided an understanding of the immune responses that correlate with protection during natural infection and vaccination. here, we infected a small group of male rhesus (macaca mulatta) and cynomolgus (maca ...202032747639
nonhuman primates exposed to zika virus in utero are not protected against reinfection at 1 year postpartum.there is limited information about the impact of zika virus (zikv) exposure in utero on the anti-zikv immune responses of offspring. we infected six rhesus macaque dams with zikv early or late in pregnancy and studied four of their offspring over the course of a year postpartum. despite evidence of zikv exposure in utero, we observed no structural brain abnormalities in the offspring. we detected infant-derived zikv-specific immunoglobulin a antibody responses and t cell memory responses during ...202033115950
two sides of a coin: a zika virus mutation selected in pregnant rhesus macaques promotes fetal infection in mice but at a cost of reduced fitness in nonpregnant macaques and diminished transmissibility by vectors.although fetal death is now understood to be a severe outcome of congenital zika syndrome, the role of viral genetics is still unclear. we sequenced zika virus (zikv) from a rhesus macaque fetus that died after inoculation and identified a single intra-host substitution, m1404i, in the zikv polyprotein, located in ns2b. targeted sequencing flanking position 1404 in 9 additional macaque mothers and their fetuses identified m1404i at sub-consensus frequency in the majority (5 of 9, 56%) of animals ...202032999034
the innate immune response in zika virus infection.zika virus (zikv; flaviviridae, flavivirus) was discovered in 1947 in uganda, africa, from the serum of a sentinel rhesus monkey (macaca mulatta). it is an enveloped, positive-sense, single-stranded rna virus, which encodes a single polyprotein that is cleaved into 10 individual proteins. in 2015, the zika-epidemic in brazil was marked mainly by the exponential growth of microcephaly cases and other congenital defects. with regard to host-pathogen relationships, understanding the role of the imm ...202032926478
zika virus in rhesus macaque semen and reproductive tract tissues: a pilot study of acute infection†.although sexual transmission of zika virus (zikv) is well-documented, the viral reservoir(s) in the male reproductive tract remains uncertain in humans and immune-intact animal models. we evaluated the presence of zikv in a rhesus macaque pilot study to determine persistence in semen, assess the impact of infection on sperm functional characteristics, and define the viral reservoir in the male reproductive tract. five adult male rhesus monkeys were inoculated with 105 pfu of asian-lineage zikv i ...202032761051
sofosbuvir shows a protective effect against vertical transmission of zika virus and the associated congenital syndrome in rhesus monkeys.the outbreaks of zika virus (zikv) infection in brazil, 2015-2016, were associated with severe congenital malformations. our translational study aimed to test the efficacy of the antiviral agent sofosbuvir (sof) against vertical transmission of zikv and the associated congenital syndrome (czs), using a rhesus monkey model. eight pregnant macaques were successfully infected during the organogenesis phase with a brazilian zikv strain; five of them received sof from two to fifteen days post-infecti ...202032649965
a zika virus primary isolate induces neuroinflammation, compromises the blood-brain barrier and upregulates cxcl12 in adult macaques.zika virus (zikv) is a flavivirus that can cause neuropathogenesis in adults and fetal neurologic malformation following the infection of pregnant women. we used a nonhuman primate model, the indian-origin rhesus macaque (irm), to gain insight into virus-associated hallmarks of zikv-induced adult neuropathology. we find that the virus causes prevalent acute and chronic neuroinflammation and chronic disruption of the blood-brain barrier (bbb) in adult animals. zikv infection resulted in specific ...202032585067
the vaccinia virus based sementis copenhagen vector vaccine against zika and chikungunya is immunogenic in non-human primates.the sementis copenhagen vector (scv) is a new vaccinia virus-derived, multiplication-defective, vaccine technology assessed herein in non-human primates. indian rhesus macaques (macaca mulatta) were vaccinated with a multi-pathogen recombinant scv vaccine encoding the structural polyproteins of both zika virus (zikv) and chikungunya virus (chikv). after one vaccination, neutralising antibody responses to zikv and four strains of chikv, representative of distinct viral genotypes, were generated. ...202032550013
a direct-acting antiviral drug abrogates viremia in zika virus-infected rhesus macaques.zika virus infection in humans has been associated with serious reproductive and neurological complications. at present, no protective antiviral drug treatment is available. here, we describe the testing and evaluation of the antiviral drug, galidesivir, against zika virus infection in rhesus macaques. we conducted four preclinical studies in rhesus macaques to assess the safety, antiviral efficacy, and dosing strategies for galidesivir (bcx4430) against zika virus infection. we treated 70 rhesu ...202032522808
long-term alterations in brain and behavior after postnatal zika virus infection in infant macaques.zika virus (zikv) infection has a profound impact on the fetal nervous system. the postnatal period is also a time of rapid brain growth, and it is important to understand the potential neurobehavioral consequences of zikv infection during infancy. here we show that postnatal zikv infection in a rhesus macaque model resulted in long-term behavioral, motor, and cognitive changes, including increased emotional reactivity, decreased social contact, loss of balance, and deficits in visual recognitio ...202032439858
isolation and detection of zika virus-infected rhesus macaques lymph node cells and splenocytes.zika virus (zikv) is a mosquito-borne viral infection that is shed in biological fluids promoting vertical and sexual transmission. recent outbreaks of zikv have been associated with an increase in adult and fetal infection-related diseases. zikv infection in rhesus macaques is considered a robust animal model for studying zika viral infection dynamics and fetal disease. a compelling feature of zikv is its ability to persist for long periods of time in immunocompetent hosts and during pregnancy, ...202032367369
a combination of two human monoclonal antibodies limits fetal damage by zika virus in macaques.human infection by zika virus (zikv) during pregnancy can lead to vertical transmission and fetal aberrations, including microcephaly. prophylactic administration of antibodies can diminish or prevent zikv infection in animal models, but whether passive immunization can protect nonhuman primates and their fetuses during pregnancy has not been determined. z004 and z021 are neutralizing monoclonal antibodies to domain iii of the envelope (ediii) of zikv. together the two antibodies protect nonpreg ...202032209664
complete protection in macaques conferred by purified inactivated zika vaccine: defining a correlate of protection.a critical global health need exists for a zika vaccine capable of mitigating the effects of future zika epidemics. in this study we evaluated the antibody responses and efficacy of an aluminum hydroxide adjuvanted purified inactivated zika vaccine (pizv) against challenge with zika virus (zikv) strain prvabc59. indian rhesus macaques received two doses of pizv at varying concentrations ranging from 0.016 µg - 10 µg and were subsequently challenged with zikv six weeks or one year following the s ...202032103097
a neonatal nonhuman primate model of gestational zika virus infection with evidence of microencephaly, seizures and cardiomyopathy.zika virus infection during pregnancy is associated with miscarriage and with a broad spectrum of fetal and neonatal developmental abnormalities collectively known as congenital zika syndrome (czs). symptomology of czs includes malformations of the brain and skull, neurodevelopmental delay, seizures, joint contractures, hearing loss and visual impairment. previous studies of zika virus in pregnant rhesus macaques (macaca mulatta) have described injury to the developing fetus and pregnancy loss, ...202031935257
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