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• W2912383155 abstract "•Development of mouse models of SPOV infection•SPOV uniquely infects feet of mice and results in acute joint swelling•Serological relatedness between SPOV, ZIKV, and DENV established•Anti-ZIKV and anti-DENV neutralizing mAbs have protective activity in vivo Spondweni virus (SPOV) is the flavivirus that is most closely related to Zika virus (ZIKV). Although SPOV causes sporadic human infections in Africa, recently it was found in Culex mosquitoes in Haiti. To investigate the pathogenic spectrum of SPOV, we developed infection models in mice. Although two SPOV strains failed to cause disease in immunocompetent mice, each accumulated in the brain, spleen, eye, testis, and kidney when type I interferon signaling was blocked and unexpectedly caused infection, immune cell infiltration, and swelling in the ankle. In pregnant mice, SPOV replicated in the placenta and fetus but did not cause placental insufficiency or microcephaly. We identified human antibodies from ZIKV or DENV immune subjects that neutralized SPOV infection and protected against lethal challenge. Our experiments describe similarities and differences in clinical syndromes between SPOV and ZIKV and suggest that their serological relatedness has implications for antibody therapeutics and flavivirus vaccine development. Spondweni virus (SPOV) is the flavivirus that is most closely related to Zika virus (ZIKV). Although SPOV causes sporadic human infections in Africa, recently it was found in Culex mosquitoes in Haiti. To investigate the pathogenic spectrum of SPOV, we developed infection models in mice. Although two SPOV strains failed to cause disease in immunocompetent mice, each accumulated in the brain, spleen, eye, testis, and kidney when type I interferon signaling was blocked and unexpectedly caused infection, immune cell infiltration, and swelling in the ankle. In pregnant mice, SPOV replicated in the placenta and fetus but did not cause placental insufficiency or microcephaly. We identified human antibodies from ZIKV or DENV immune subjects that neutralized SPOV infection and protected against lethal challenge. Our experiments describe similarities and differences in clinical syndromes between SPOV and ZIKV and suggest that their serological relatedness has implications for antibody therapeutics and flavivirus vaccine development. Spondweni virus (SPOV), a member of the same serogroup as Zika virus (ZIKV), is a mosquito-transmitted flavivirus that historically has circulated in sub-Saharan Africa. In 1952, the Chuku strain of SPOV was isolated from a patient in Nigeria, but cross-reactivity in neutralization tests led to its initial misclassification as a ZIKV strain. Until subsequent analysis clarified the identity of SPOV-Chuku (Draper, 1965Draper C.C. Infection with the Chuku strain of Spondweni virus.West Afr. Med. J. 1965; 14: 16-19Google Scholar), the 1955 South African SPOV-SA Ar94 mosquito isolate was considered the prototype SPOV strain (Kokernot et al., 1957Kokernot R.H. Smithburn K.C. Muspratt J. Hodgson B. Studies on arthropod-borne viruses of Tongaland. VIII. Spondweni virus, an agent previously unknown, isolated from Taeniorhynchus (Mansonioides) uniformis.S. Afr. J. Med. Sci. 1957; 22: 103-112Google Scholar, MacNamara, 1954MacNamara F.N. Zika virus: a report on three cases of human infection during an epidemic of jaundice in Nigeria.Trans. R. Soc. Trop. Med. Hyg. 1954; 48: 139-145Google Scholar). Although most symptomatic SPOV infections result in mild illness, a subset of cases are believed to progress to more serious disease, including vascular leakage and neurological involvement (Haddow and Woodall, 2016Haddow A.D. Woodall J.P. Distinguishing between Zika and Spondweni viruses.Bull. World Health Organ. 2016; 94 (711–711A)Google Scholar). The enzootic cycle of SPOV is not entirely defined, but it is likely propagated between mosquitoes and non-human primates (Haddow et al., 2016Haddow A.D. Nasar F. Guzman H. Ponlawat A. Jarman R.G. Tesh R.B. Weaver S.C. Genetic characterization of Spondweni and Zika viruses and susceptibility of geographically distinct strains of Aedes aegypti, Aedes albopictus and Culex quinquefasciatus (Diptera: Culicidae) to Spondweni virus.PLoS Negl. Trop. Dis. 2016; 10: e0005083Google Scholar). In contrast to other flaviviruses (e.g., Dengue, Zika, and West Nile viruses), SPOV infection and dissemination historically was low or non-existent in Aedes aegypti, Aedes albopictus, and Culex quinquefasciatus mosquitoes following infectious blood feeding of SPOV strains (Haddow et al., 2016Haddow A.D. Nasar F. Guzman H. Ponlawat A. Jarman R.G. Tesh R.B. Weaver S.C. Genetic characterization of Spondweni and Zika viruses and susceptibility of geographically distinct strains of Aedes aegypti, Aedes albopictus and Culex quinquefasciatus (Diptera: Culicidae) to Spondweni virus.PLoS Negl. Trop. Dis. 2016; 10: e0005083Google Scholar). However, isolations of SPOV from eight other species of mosquitoes in the genera Aedes, Culex, Eretmapodites, and Mansonia have been reported. Based on its vector biology, it has been speculated that SPOV has limited potential for urban epidemic cycles (Haddow et al., 2016Haddow A.D. Nasar F. Guzman H. Ponlawat A. Jarman R.G. Tesh R.B. Weaver S.C. Genetic characterization of Spondweni and Zika viruses and susceptibility of geographically distinct strains of Aedes aegypti, Aedes albopictus and Culex quinquefasciatus (Diptera: Culicidae) to Spondweni virus.PLoS Negl. Trop. Dis. 2016; 10: e0005083Google Scholar). However, the epidemiology may be changing, as recently, SPOV was detected in field-caught Culex quinquefasciatus mosquitoes in Haiti in 2016 (White et al., 2018White S.K. Lednicky J.A. Okech B.A. Morris Jr., J.G. Dunford J.C. Spondweni virus in field-caught Culex quinquefasciatus mosquitoes, Haiti, 2016.Emerg. Infect. Dis. 2018; 24: 1765-1767Google Scholar). SPOV has a positive-sense, single-stranded RNA genome of approximately 11 kb in length (Pierson and Diamond, 2013Pierson T.C. Diamond M.S. Flaviviruses.in: Knipe D.M. Howley P.M. Fields Virology. Lippincott Williams & Wilkins, 2013: 747-794Google Scholar). SPOV-Chuku and SPOV-SA Ar94 share ∼98% nucleotide and 99% amino acid identity to each other and ∼68% nucleotide and 75% amino acid identity to ZIKV, the closest flavivirus relative (Haddow et al., 2016Haddow A.D. Nasar F. Guzman H. Ponlawat A. Jarman R.G. Tesh R.B. Weaver S.C. Genetic characterization of Spondweni and Zika viruses and susceptibility of geographically distinct strains of Aedes aegypti, Aedes albopictus and Culex quinquefasciatus (Diptera: Culicidae) to Spondweni virus.PLoS Negl. Trop. Dis. 2016; 10: e0005083Google Scholar). Sequencing of RNA from SPOV-infected mosquitoes from Haiti revealed 96.8% and 98.8% nucleotide and 98.3% and 98.8% amino acid identity with SPOV-Chuku and SPOV-SA Ar94 strains, respectively (White et al., 2018White S.K. Lednicky J.A. Okech B.A. Morris Jr., J.G. Dunford J.C. Spondweni virus in field-caught Culex quinquefasciatus mosquitoes, Haiti, 2016.Emerg. Infect. Dis. 2018; 24: 1765-1767Google Scholar). Despite the close genetic relationship to ZIKV, little is known regarding the pathogenesis of SPOV infections and its clinical syndromes. Here, we investigated the tropism and disease potential of SPOV in mice. SPOV, like ZIKV (Lazear et al., 2016Lazear H.M. Govero J. Smith A.M. Platt D.J. Fernandez E. Miner J.J. Diamond M.S. A mouse model of Zika virus pathogenesis.Cell Host Microbe. 2016; 19: 720-730Google Scholar, Rossi et al., 2016Rossi S.L. Tesh R.B. Azar S.R. Muruato A.E. Hanley K.A. Auguste A.J. Langsjoen R.M. Paessler S. Vasilakis N. Weaver S.C. Characterization of a novel murine model to study Zika virus.Am. J. Trop. Med. Hyg. 2016; 94: 1362-1369Google Scholar), did not replicate efficiently in wild-type (WT) C57BL/6 immunocompetent mice after subcutaneous inoculation. However, administration of an anti-Ifnar1 blocking monoclonal antibody (mAb) rendered animals susceptible to infection and disease by the two prototype strains, SPOV-Chuku and SPOV-SA Ar94. Mice treated with anti-Ifnar1 mAb sustained high levels of SPOV infection in multiple tissues, including serum, spleen, kidney, and brain at 7, 14, and 21 days post-infection (dpi). Unexpectedly, persistent viral RNA was measured in the serum up to 56 dpi, and this finding occurred despite the induction of adaptive B and T cell responses. Moreover, both SPOV strains had the capacity to induce foot swelling, which is not typical of flaviviruses and is instead reminiscent of the musculoskeletal disease observed following alphavirus infection (Morrison et al., 2011Morrison T.E. Oko L. Montgomery S.A. Whitmore A.C. Lotstein A.R. Gunn B.M. Elmore S.A. Heise M.T. A mouse model of chikungunya virus-induced musculoskeletal inflammatory disease: evidence of arthritis, tenosynovitis, myositis, and persistence.Am. J. Pathol. 2011; 178: 32-40Google Scholar). We also assessed the ability of SPOV to infect the placenta and developing fetus in the context of pregnancy. Although SPOV was detected in the placenta and fetal head at embryonic day (E)13.5, overt fetal pathology was not observed. Finally, our studies discerned the serological relatedness of SPOV, ZIKV, and DENV and established that cross-reactive anti-ZIKV and anti-DENV human mAbs can neutralize SPOV infection in cell culture and protect against disease in vivo. Collectively, our studies establish disease models of SPOV pathogenesis in mice and define potential protective countermeasures with therapeutic antibodies. To begin to understand whether SPOV causes a similar disease pathogenesis to the closely related ZIKV, we developed a mouse model of infection. Although a recent study used AG129 mice lacking both type I interferon (IFN) (α/β) and II IFN (γ) receptors to assess SPOV tropism in the male reproductive tract (McDonald et al., 2017McDonald E.M. Duggal N.K. Brault A.C. Pathogenesis and sexual transmission of Spondweni and Zika viruses.PLoS Negl. Trop. Dis. 2017; 11: e0005990Google Scholar), we sought to establish a less immunocompromised model, which might have greater utility in evaluating viral pathogenesis and host immune responses. Groups of 8-week-old male C57BL/6 mice were treated with an anti-Ifnar1-blocking mAb (MAR1-5A3) 1 day prior to subcutaneous inoculation in the foot with prototype SPOV strains SA Ar94 (South Africa, 1955) or Chuku (Nigeria, 1952; Figure 1). Of note, contemporary infectious isolates from Haiti are not yet available. We confirmed the identity of SPOV SA Ar94 and SPOV-Chuku strains by next-generation sequencing and also established that no other adventitious pathogens were present in our viral stocks. Mice that did not receive anti-Ifnar1 mAb exhibited no weight loss, morbidity, or mortality after inoculation with either SPOV strain (Figures 1A–1D). In comparison, mice inoculated with SPOV-SA Ar94 and pretreated with 0.5, 1, or 2 mg of anti-Ifnar1 mAb had 33%, 66%, and 100% mortality rates, respectively (Figure 1A). Mice inoculated with SPOV-Chuku had lethality rates of 66%–90% when pretreated with 0.5 or 1 mg of anti-Ifnar1 mAb (Figure 1C). Consistent with these results, mice that ultimately succumbed to infection began to lose weight by 5 dpi with either SPOV-SA Ar94 or SPOV-Chuku. By 9 (SPOV-SA Ar94) or 12 (SPOV-Chuku) dpi, animals had lost between 15% and 30% of their starting body weight (Figures 1B and 1D). We also investigated the pathogenic potential of SPOV in 3-week-old male mice in which the human STAT2 gene was introduced into the mouse STAT2 locus (hSTAT2 KI) in the absence of anti-Ifnar1 mAb treatment; these mice were tested because they enabled ZIKV to overcome murine innate immune restriction and cause pathogenesis (Gorman et al., 2018Gorman M.J. Caine E.A. Zaitsev K. Begley M.C. Weger-Lucarelli J. Uccellini M.B. Tripathi S. Morrison J. Yount B.L. Dinnon 3rd, K.H. et al.An immunocompetent mouse model of Zika virus infection.Cell Host Microbe. 2018; 23: 672-685.e6Scopus (0) Google Scholar). However, unlike ZIKV, SPOV NS5 protein did not promote degradation of human STAT2; nonetheless, SPOV NS5 did bind human STAT2, which could antagonize its innate immune functions through other mechanisms (Grant et al., 2016Grant A. Ponia S.S. Tripathi S. Balasubramaniam V. Miorin L. Sourisseau M. Schwarz M.C. Sánchez-Seco M.P. Evans M.J. Best S.M. García-Sastre A. Zika virus targets human STAT2 to inhibit type I interferon signaling.Cell Host Microbe. 2016; 19: 882-890Google Scholar). In contrast to results with ZIKV, hSTAT2 KI mice did not exhibit weight loss, morbidity, or mortality and sustained little viral infection at 7 dpi with SPOV-SA Ar94 (Figure S1). In the course of the infection studies of WT C57BL/6 mice, we noticed swelling in the feet of mice inoculated with SPOV-SA Ar94 (Figures 1E and 1F) or SPOV-Chuku (Figures 1G and 1H). SPOV-SA Ar94 caused modest swelling (10%–20% increase in size) in the ipsilateral foot at 5 dpi and only when anti-Ifnar1 mAb was administered. In comparison, mice infected with SPOV-Chuku and pretreated with 0.5 or 1 mg of anti-Ifnar1 mAb had approximately 50% or 80% increases in ipsilateral foot size at 5 dpi, respectively (Figure 1I). Remarkably, the contralateral foot also developed swelling after SPOV-Chuku infection, with an approximately 10%–20% increase in size at 5 dpi when the mice were pretreated with 0.5 or 1 mg of anti-Ifnar1, respectively. Flow cytometric analysis of the ipsilateral foot at 5 dpi revealed a substantial increase in immune cell infiltration in mice pretreated with 1 mg of anti-Ifnar1 and inoculated with SPOV-Chuku in comparison to mock-infected, anti-Ifnar1-treated control animals (Figure 1J). We observed a greater than 300-fold increase in CD45+ leukocytes in the feet of SPOV-Chuku-infected animals, with markedly higher numbers of monocytes, neutrophils, NK cells, CD8+ T cells, CD4+ T cells, and B cells in the joint-associated tissues. We assessed the tissue tropism of SPOV by measuring the viral burden at 7, 14, and 21 dpi. SPOV strains replicated inefficiently in WT mice without anti-Ifnar1 mAb pretreatment, with levels of viral RNA (Table S1) above background observed consistently only in the ipsilateral foot at 7 dpi. In comparison, mice pretreated with 0.5 or 1 mg of anti-Ifnar1 mAb had approximately 103 to 105 FFU equivalents/g of SPOV-SA Ar94 or SPOV-Chuku in the serum, brain, spleen, testes, kidney, ileum, and eye at 7 dpi (Figures 2A and 2B ). Mice inoculated with SPOV-SA Ar94 or SPOV-Chuku both sustained high levels of SPOV RNA (105–106 FFU equivalents/g) in the ipsilateral and contralateral feet at 7 dpi. At 14 dpi, mice infected with SPOV-SA Ar94 or SPOV-Chuku and treated with 0.5 mg anti-Ifnar1 mAb generally showed waning titers with a ∼10-fold reduction in viral RNA in most tissues compared to 7 dpi (Figures 2C and 2D). By 21 dpi, most mice inoculated with SPOV-SA Ar94 had cleared infection in the ileum and eye yet still showed residual viral RNA in the serum, spleen, and brain (Figure 2E). Mice infected with SPOV-Chuku sustained greater viral persistence at 21 dpi in several sites, including the serum, brain, spleen, and feet (Figure 2F). Because of the persistent viremia at 21 dpi, we performed a longitudinal study in mice treated with 0.5 mg of anti-Ifnar1 mAb and inoculated with SPOV-SA Ar94. Remarkably, viremia was detected in serum until approximately 56 dpi (Figure 2G). Given the unexpected persistence of SPOV in some tissues, we evaluated B and T cell responses and compared them to those observed after ZIKV infection. WT mice were pretreated with 0.5 mg of anti-Ifnar1-blocking mAb, inoculated with SPOV-SA Ar94 or ZIKV (Dakar 41525), and ex vivo responses of splenic T cells were assessed 8 days later, utilizing a Db-restricted immunodominant ZIKV-derived 9-mer peptide (E294–302; Elong Ngono et al., 2017Elong Ngono A. Vizcarra E.A. Tang W.W. Sheets N. Joo Y. Kim K. Gorman M.J. Diamond M.S. Shresta S. Mapping and role of the CD8+ T cell response during primary Zika virus infection in mice.Cell Host Microbe. 2017; 21: 35-46Google Scholar) that cross-reacts with SPOV (Figure 3A). The corresponding SPOV E protein peptide has three differences at amino acids 296 (p3 of the peptide: valine to isoleucine), 297 (p4: serine to glycine), and 302 (p9: valine to isoleucine); these changes do not alter or are compatible with anchor residues at p2 and p9 (Falk et al., 1991Falk K. Rötzschke O. Stevanović S. Jung G. Rammensee H.G. Allele-specific motifs revealed by sequencing of self-peptides eluted from MHC molecules.Nature. 1991; 351: 290-296Google Scholar). Relative to uninfected mice, the numbers of CD8+ T cells expressing the cytotoxicity marker granzyme B were increased and similar between SPOV- and ZIKV-infected mice. The numbers of CD8+ T cells expressing IFNγ after peptide restimulation were increased in ZIKV-infected mice relative to SPOV-infected mice, which could reflect the sequence mismatch of the peptide used for restimulation. Notwithstanding this difference, SPOV-infected mice clearly had a higher number of IFNγ+ CD8+ T cells than naive mice. Together, with the granzyme B responses, this finding confirmed induction of antigen-specific CD8+ T cell responses in SPOV-infected mice. Differences in the frequency or total number of CD4+ T cells were not observed among the three groups (Figure 3A). Because of the persistent viremia, we evaluated the humoral immune responses. Initially, we assessed the antiviral antibody response at days 7, 14, and 21 after SPOV-SA Ar94 inoculation of mice that were not treated or treated with anti-Infar1 mAb. Serum from mice that did not receive anti-Ifnar1 mAb had higher neutralizing antibody titers at 14 and 21 dpi compared to 0 and 7 dpi (Figure 3B). Serum from mice treated with 0.5 mg of anti-Ifnar1 mAb prior to SPOV-SA Ar94 infection showed neutralizing activity at 7 dpi, which plateaued thereafter (Figure 3C). To extend these findings, in animals infected with SPOV and treated with anti-Ifnar1 mAb, we measured the antiviral immunoglobulin M (IgM) and IgG responses in serum by ELISA using purified, recombinant ectodomain (amino acids 2–412) of SPOV E protein (Figures 3D and 3E). IgM levels peaked at 7 dpi and then decreased over time, whereas IgG levels peaked at 14 dpi and were similar at 21 dpi. As the lack of augmentation of the anti-SPOV IgG response after day 14 might contribute to the persistent viremia, we compared the antibody response after ZIKV infection, where viremia in serum is cleared within 21 dpi (Govero et al., 2016Govero J. Esakky P. Scheaffer S.M. Fernandez E. Drury A. Platt D.J. Gorman M.J. Richner J.M. Caine E.A. Salazar V. et al.Zika virus infection damages the testes in mice.Nature. 2016; 540: 438-442Scopus (367) Google Scholar). However, similar to SPOV, serum from ZIKV-infected mice pretreated with anti-Ifnar1-blocking mAb reached peak neutralizing antibody titer at 7 dpi and did not increase further at 14 and 21 dpi (Figure 3F). An ELISA with purified ZIKV E ectodomain protein showed peak IgM levels at 7 dpi (Figure 3G) and constant levels of ZIKV-specific IgG levels at 7, 14, and 21 dpi (Figure 3H), results that were analogous to those seen after SPOV infection. Thus, in mice treated with anti-Ifnar1 mAb, SPOV and ZIKV infection induced similar humoral responses, yet viremia persisted for a longer duration after SPOV infection. To determine whether SPOV has a similar potential for causing placental damage and fetal demise as ZIKV, we adapted a model of ZIKV infection during pregnancy (Miner et al., 2016Miner J.J. Cao B. Govero J. Smith A.M. Fernandez E. Cabrera O.H. Garber C. Noll M. Klein R.S. Noguchi K.K. et al.Zika virus infection during pregnancy in mice causes placental damage and fetal demise.Cell. 2016; 165: 1081-1091Google Scholar). WT dams were treated with either 0, 0.5, or 1 mg of anti-Ifnar1 mAb on E5.5, inoculated with SPOV-SA Ar94 on E6.5 via footpad injection, and maternal and fetal tissues were collected on E13.5 (Figure 4). The levels of SPOV RNA roughly correlated with the dose of anti-Ifnar1 mAb administered, with a trend toward higher levels of SPOV RNA in the serum and brain in dams receiving the 1 mg dose. However, levels of SPOV RNA in the spleen at 7 dpi were similar in dams receiving 0.5 or 1 mg of anti-Ifnar1 mAb (Figure 4A). Dams that did not receive anti-Ifnar1 mAb sustained minimal or no SPOV infection in maternal or fetal tissues. Dams treated with anti-Ifnar1 mAb and inoculated with SPOV showed placental infection and vertical transmission to the developing fetus. Generally, higher amounts of SPOV RNA were detected in the placentas compared to the fetal heads (Figure 4B), and infectious virus (∼105–106 plaque-forming units [PFU]/g) was recovered only from the placentas and not the fetal heads (Figure 4C). Given the high levels of SPOV RNA in the placenta yet relatively low levels in fetal heads, we performed RNA in situ hybridization (ISH) to better define the tropism of infection. We detected isolated SPOV RNA-positive cells that localized predominantly to the junctional zone of the placenta in dams treated with anti-Ifnar1 mAb (Figure 4D). This pattern of viral RNA staining is similar to ZIKV infection at a similar gestational time point (Jagger et al., 2017Jagger B.W. Miner J.J. Cao B. Arora N. Smith A.M. Kovacs A. Mysorekar I.U. Coyne C.B. Diamond M.S. Gestational Stage and IFN-lambda Signaling Regulate ZIKV Infection In Utero.Cell Host Microbe. 2017; 22: 366-376.e363Google Scholar). However, we did not observe significant differences in the fraction of resorbed fetuses in the SPOV-infected dams at E13.5 or E18 relative to the uninfected dams (Figures 4E and 4F). There also were no differences in occipital-frontal fetal head diameter or fetus length at E13.5 when comparing SPOV-infected and uninfected groups (Figures 4G and 4H). Thus, although SPOV is capable of propagating at the maternal-fetal interface, unlike ZIKV (Miner et al., 2016Miner J.J. Cao B. Govero J. Smith A.M. Fernandez E. Cabrera O.H. Garber C. Noll M. Klein R.S. Noguchi K.K. et al.Zika virus infection during pregnancy in mice causes placental damage and fetal demise.Cell. 2016; 165: 1081-1091Google Scholar), it does not appear to cause extensive placental damage or fetal demise in mice. To confirm the functional relationship of antibody responses to SPOV and explore the potential for cross-neutralization or enhancement of related flaviviruses (e.g., ZIKV and DENV), we tested sera from convalescent mice after ZIKV or SPOV infection for their ability to inhibit SPOV, ZIKV, or DENV2 infection (Figures 5A–5C and S2). Neutralization was evaluated using reporter virus particles (RVPs) produced with the structural proteins of each flavivirus. As expected, naive sera failed to neutralize or enhance SPOV, ZIKV, or DENV2 RVPs (Figures 5A and S2). ZIKV-immune mouse sera strongly neutralized ZIKV (serum dilution EC50 of 1/14,049) and moderately neutralized SPOV (EC50 of 1/499) but showed little inhibition against DENV2 (EC50 < 1/100; Figures 5B and S2). In contrast, SPOV-immune murine sera strongly neutralized SPOV (EC50 of 1/5,009) and moderately neutralized ZIKV (EC50 of 1/327) but showed little inhibitory activity against DENV2 (EC50 < 1/100; Figures 5C and S2). Sub-neutralizing levels of ZIKV- or SPOV-immune sera enhanced infection of all three flaviviruses in cells expressing Fcγ receptors (Figure S2). Because ADE and neutralization of flaviviruses are a function of multiple-hit model of antibody occupancy of the virion, within a given FcγR-expressing cell population near the threshold of neutralization, ADE is observed in some cells whereas neutralization occurs in others (Pierson et al., 2007Pierson T.C. Xu Q. Nelson S. Oliphant T. Nybakken G.E. Fremont D.H. Diamond M.S. The stoichiometry of antibody-mediated neutralization and enhancement of West Nile virus infection.Cell Host Microbe. 2007; 1: 135-145Google Scholar). These functional data confirm that ZIKV and SPOV are distinct viruses within the same serogroup and that cross-reactive polyclonal antibodies (pAbs) derived from murine infections can enhance ZIKV, SPOV, and DENV infection in cell culture. We next tested sera from convalescent humans after ZIKV or DENV infection for their ability to inhibit or enhance SPOV, ZIKV, or DENV2 infection (Figures 5D, S3, and S4). Sera from convalescent ZIKV-infected individuals most potently inhibited ZIKV (EC50 of 1/7,822), moderately inhibited SPOV (EC50 of 1/564), and exhibited low neutralizing activity against DENV2 (EC50 < 1/60). One individual may have had previous flavivirus exposure, as the serum neutralized ZIKV and DENV2 RVPs at similar titers (EC50 of 1/3,568). Sera from convalescent DENV-infected individuals moderately neutralized DENV2 (EC50 of 1/337) and weakly inhibited ZIKV (EC50 of 1/90) but had little blocking activity against SPOV (EC50 < 1/30). In comparison, convalescent human sera from ZIKV- or DENV-infected individuals enhanced infection of all three flaviviruses (Figures S3 and S4). Given the serological data, we predicted that a subset of cross-reactive mAbs might neutralize SPOV infection in cell culture and protect in vivo. E-dimer epitope (EDE) mAbs isolated from DENV-infected patients bind to an inter-dimer quaternary epitope and cross-neutralize ZIKV infection (Barba-Spaeth et al., 2016Barba-Spaeth G. Dejnirattisai W. Rouvinski A. Vaney M.C. Medits I. Sharma A. Simon-Lorière E. Sakuntabhai A. Cao-Lormeau V.M. Haouz A. et al.Structural basis of potent Zika-dengue virus antibody cross-neutralization.Nature. 2016; 536: 48-53Google Scholar, Dejnirattisai et al., 2015Dejnirattisai W. Wongwiwat W. Supasa S. Zhang X. Dai X. Rouvinski A. Jumnainsong A. Edwards C. Quyen N.T. Duangchinda T. et al.A new class of highly potent, broadly neutralizing antibodies isolated from viremic patients infected with dengue virus.Nat. Immunol. 2015; 16: 170-177Google Scholar, Dejnirattisai et al., 2016Dejnirattisai W. Supasa P. Wongwiwat W. Rouvinski A. Barba-Spaeth G. Duangchinda T. Sakuntabhai A. Cao-Lormeau V.M. Malasit P. Rey F.A. et al.Dengue virus sero-cross-reactivity drives antibody-dependent enhancement of infection with zika virus.Nat. Immunol. 2016; 17: 1102-1108Scopus (463) Google Scholar, Fernandez et al., 2017Fernandez E. Dejnirattisai W. Cao B. Scheaffer S.M. Supasa P. Wongwiwat W. Esakky P. Drury A. Mongkolsapaya J. Moley K.H. et al.Human antibodies to the dengue virus E-dimer epitope have therapeutic activity against Zika virus infection.Nat. Immunol. 2017; 18: 1261-1269Google Scholar). Indeed, EDE1 mAbs (e.g., EDE1-B10, EDE1-A9, and EDE1-C4) strongly inhibited infection of SPOV in cell culture (EC50 of 7, 131, and 23 ng/mL, respectively; Figure 6A). We separately screened a panel of human anti-ZIKV-neutralizing mAbs (Sapparapu et al., 2016Sapparapu G. Fernandez E. Kose N. Bin Cao Fox J.M. Bombardi R.G. Zhao H. Nelson C.A. Bryan A.L. Barnes T. et al.Neutralizing human antibodies prevent Zika virus replication and fetal disease in mice.Nature. 2016; 540: 443-447Google Scholar) for their ability to inhibit SPOV infection. ZIKV-117 (DII-dimer epitope), ZIKV-A7 (DIII epitope), and ZIKV-C10 (DIII epitope) neutralized SPOV infection (EC50 of ∼384, 72, and 174 ng/mL, respectively), albeit less efficiently than ZIKV (EC50 of ∼9, 48, and 403 ng/mL, respectively, against ZIKV-Brazil; Sapparapu et al., 2016Sapparapu G. Fernandez E. Kose N. Bin Cao Fox J.M. Bombardi R.G. Zhao H. Nelson C.A. Bryan A.L. Barnes T. et al.Neutralizing human antibodies prevent Zika virus replication and fetal disease in mice.Nature. 2016; 540: 443-447Google Scholar). LALA variants of EDE1-B10 and ZIKV-117, which inefficiently engage activating Fcγ receptors (Hessell et al., 2007Hessell A.J. Hangartner L. Hunter M. Havenith C.E. Beurskens F.J. Bakker J.M. Lanigan C.M. Landucci G. Forthal D.N. Parren P.W. et al.Fc receptor but not complement binding is important in antibody protection against HIV.Nature. 2007; 449: 101-104Google Scholar; Figure 6B), had similar neutralization profiles as their WT counterparts (Figure 6A). We tested the cross-neutralizing anti-DENV and anti-ZIKV mAbs for their ability to protect mice against SPOV infection. In 8-week-old WT C57BL/6 mice, we passively transferred 1 mg of anti-Ifnar1-blocking mAb and a single 100 μg dose (∼4 mg/kg) of EDE1-B10, ZIKV-117, ZIKV-A7, EDE1-A9, EDE1-C4, ZIKV-C10, or an isotype control mAb (hu-CHK-152) 1 day prior to SPOV-SA Ar94 inoculation. Mice treated with EDE1-A9, EDE1-B10, EDE1-C4, and ZIKV-117 were completely protected against lethal infection and weight loss (Figures 6C and 6D). In comparison, mice treated with ZIKV-A7 or ZIKV-C10 were protected only partially with some weight loss and lethality observed. We evaluated two of the protective mAbs, EDE1-B10 and ZIKV-117, for their efficacy as post-exposure therapy by assessing impact on weight loss, mortality, and SPOV burden in tissues. 8-week-old WT mice were given anti-Ifnar1 mAb 1 day prior to inoculation with SPOV-SA Ar94. Mice treated with a single 100 μg (∼4 mg/kg) dose of EDE1-B10 or ZIKV-117 mAbs 1 day after SPOV inoculation sustained no weight loss and low (10%) rates of mortality compared to animals treated with the isotype control hu-CHK-152 mAb (Figures 6E and 6F). We also assessed therapeutic effects on viral burden at 7 dpi using parental or LALA variants of EDE1-B10 or ZIKV-117 mAbs or hu-CHK-152 control mAb (Figures 6G–6M). EDE1-B10 parental and LALA mAbs both controlled infection equivalently with markedly reduced or undetectable viral RNA levels measured in the serum, brain, spleen, testis, kidney, ileum, and eye. This finding suggests that the majority of the protection afforded by EDE1-B10 mAbs is independent of Fc effector functions and likely due to neutralizing activity. ZIKV-117 mAb therapy also reduced SPOV infection in" @default.
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• W2912383155 date "2019-02-01" @default.
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• W2912383155 title "Dengue and Zika Virus Cross-Reactive Human Monoclonal Antibodies Protect against Spondweni Virus Infection and Pathogenesis in Mice" @default.
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• W2912383155 doi "https://doi.org/10.1016/j.celrep.2019.01.052" @default.
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