scholarly journals Neutralizing human monoclonal antibodies prevent Zika virus infection in macaques

2017 ◽  
Vol 9 (410) ◽  
pp. eaan8184 ◽  
Author(s):  
Diogo M. Magnani ◽  
Thomas F. Rogers ◽  
Nathan Beutler ◽  
Michael J. Ricciardi ◽  
Varian K. Bailey ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Virus Infection ◽  
Pregnant Women ◽  
Receptor Binding ◽  
Zika Virus ◽  
Infected Patient ◽  
Nonhuman Primates ◽  
Fcγ Receptor ◽  
Human Monoclonal Antibodies ◽  
Zikv Infection

Therapies to prevent maternal Zika virus (ZIKV) infection and its subsequent fetal developmental complications are urgently required. We isolated three potent ZIKV-neutralizing monoclonal antibodies (nmAbs) from the plasmablasts of a ZIKV-infected patient—SMZAb1, SMZAb2, and SMZAb5—directed against two different domains of the virus. We engineered these nmAbs with Fc LALA mutations that abrogate Fcγ receptor binding, thus eliminating potential therapy-mediated antibody-dependent enhancement. We administered a cocktail of these three nmAbs to nonhuman primates 1 day before challenge with ZIKV and demonstrated that the nmAbs completely prevented viremia in serum after challenge. Given that numerous antibodies have exceptional safety profiles in humans, the cocktail described here could be rapidly developed to protect uninfected pregnant women and their fetuses.

scholarly journals Dengue and Zika Virus Cross-Reactive Human Monoclonal Antibodies Protect against Spondweni Virus Infection and Pathogenesis in Mice

Cell Reports ◽  
2019 ◽  
Vol 26 (6) ◽  
pp. 1585-1597.e4 ◽  
Author(s):  
Vanessa Salazar ◽  
Brett W. Jagger ◽  
Juthathip Mongkolsapaya ◽  
Katherine E. Burgomaster ◽  
Wanwisa Dejnirattisai ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Virus Infection ◽  
Zika Virus ◽  
Human Monoclonal Antibodies

scholarly journals Dengue Virus Envelope Dimer Epitope Monoclonal Antibodies Isolated from Dengue Patients Are Protective against Zika Virus

mBio ◽  
2016 ◽  
Vol 7 (4) ◽  
Author(s):  
J. A. Swanstrom ◽  
J. A. Plante ◽  
K. S. Plante ◽  
E. F. Young ◽  
E. McGowan ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Dengue Virus ◽  
Pregnant Women ◽  
Zika Virus ◽  
Neutralizing Antibodies ◽  
Severe Disease ◽  
Fetal Loss ◽  
Human Monoclonal Antibodies ◽  
Serum Dilution ◽  
Homologous Virus

ABSTRACT Zika virus (ZIKV) is a mosquito-borne flavivirus responsible for thousands of cases of severe fetal malformations and neurological disease since its introduction to Brazil in 2013. Antibodies to flaviviruses can be protective, resulting in lifelong immunity to reinfection by homologous virus. However, cross-reactive antibodies can complicate flavivirus diagnostics and promote more severe disease, as noted after serial dengue virus (DENV) infections. The endemic circulation of DENV in South America and elsewhere raises concerns that preexisting flavivirus immunity may modulate ZIKV disease and transmission potential. Here, we report on the ability of human monoclonal antibodies and immune sera derived from dengue patients to neutralize contemporary epidemic ZIKV strains. We demonstrate that a class of human monoclonal antibodies isolated from DENV patients neutralizes ZIKV in cell culture and is protective in a lethal murine model. We also tested a large panel of convalescent-phase immune sera from humans exposed to primary and repeat DENV infection. Although ZIKV is most closely related to DENV compared to other human-pathogenic flaviviruses, most DENV immune sera (73%) failed to neutralize ZIKV, while others had low (50% effective concentration [EC 50 ], <1:100 serum dilution; 18%) or moderate to high (EC 50 , >1:100 serum dilution; 9%) levels of cross-neutralizing antibodies. Our results establish that ZIKV and DENV share epitopes that are targeted by neutralizing, protective human antibodies. The availability of potently neutralizing human monoclonal antibodies provides an immunotherapeutic approach to control life-threatening ZIKV infection and also points to the possibility of repurposing DENV vaccines to induce cross-protective immunity to ZIKV. IMPORTANCE ZIKV is an emerging arbovirus that has been associated with severe neurological birth defects and fetal loss in pregnant women and Guillain-Barré syndrome in adults. Currently, there is no vaccine or therapeutic for ZIKV. The identification of a class of antibodies (envelope dimer epitope 1 [EDE1]) that potently neutralizes ZIKV in addition to all four DENV serotypes points to a potential immunotherapeutic to combat ZIKV. This is especially salient given the precedent of antibody therapy to treat pregnant women infected with other viruses associated with microcephaly, such as cytomegalovirus and rubella virus. Furthermore, the identification of a functionally conserved epitope between ZIKV and DENV raises the possibility that a vaccine may be able to elicit neutralizing antibodies against both viruses.

scholarly journals Monoclonal Antibodies against Zika Virus NS1 Protein Confer Protection via Fcγ Receptor-Dependent and -Independent Pathways

mBio ◽  
2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Lei Yu ◽  
Xinglong Liu ◽  
Xianmiao Ye ◽  
Wan Su ◽  
Xiaoyan Zhang ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Zika Virus ◽  
Nonstructural Protein ◽  
Effector Function ◽  
Protective Effects ◽  
Ns1 Protein ◽  
Fcγ Receptor ◽  
Zikv Infection ◽  
Effector Cells ◽  
Nonstructural Protein 1

ABSTRACT Zika virus (ZIKV) infection during pregnancy causes congenital defects such as fetal microcephaly. Monoclonal antibodies (MAbs) against the nonstructural protein 1 (NS1) have the potential to suppress ZIKV pathogenicity without enhancement of disease, but the pathways through which they confer protection remain obscure. Here, we report two types of NS1-targeted human MAbs that inhibit ZIKV infection through distinct mechanisms. MAbs 3G2 and 4B8 show a better efficacy than MAb 4F10 in suppressing ZIKV infection in C57BL/6 neonatal mice. Unlike MAb 4F10 that mainly triggers antibody-dependent cell-mediated cytotoxicity (ADCC), MAbs 3G2 and 4B8 not only trigger ADCC but inhibit ZIKV infection without Fcγ receptor-bearing effector cells, possibly at postentry stages. Destroying the Fc-mediated effector function of MAbs 3G2 and 4B8 reduces but does not abolish their protective effects, whereas destroying the effector function of MAb 4F10 eliminates the protective effects, suggesting that MAbs 3G2 and 4B8 engage both Fcγ receptor-dependent and -independent pathways. Further analysis reveals that MAbs 3G2 and 4B8 target the N-terminal region of NS1 protein, whereas MAb 4F10 targets the C-terminal region, implying that the protective efficacy of an NS1-targeted MAb may be associated with its epitope recognition. Our results illustrate that NS1-targeted MAbs have multifaceted protective effects and provide insights for the development of NS1-based vaccines and therapeutics. IMPORTANCE Zika virus (ZIKV) is a mosquito-borne flavivirus that has been linked to congenital microcephaly during recent epidemics. No licensed antiviral drug or vaccine is available. Monoclonal antibodies (MAbs) against the nonstructural protein 1 (NS1) inhibit ZIKV pathogenicity but do not enhance the disease as envelope protein-targeted MAbs do. However, the protection mechanisms are not fully understood. Here, we show that in the presence or absence of Fcγ receptor-bearing effector cells, NS1-targeted human MAbs 3G2 and 4B8 inhibit ZIKV infection. Compared to MAb 4F10 that has no inhibitory effects without effector cells, 3G2 and 4B8 confer better protection in ZIKV-infected neonatal mice. Destroying the Fc-mediated effector function reduces but does not abolish the protection of 3G2 and 4B8, suggesting that they engage both Fcγ receptor-dependent and -independent pathways. The protective efficacy of NS1-targeted MAbs may be associated with their epitope recognition. Our findings will help to develop NS1-based vaccines and therapeutics.

scholarly journals Defining Zika virus infection in pregnant women

2019 ◽  
Vol 113 (7) ◽  
pp. 290-290
Author(s):  
Carlo Ticconi ◽  
Giovanni Rezza
Keyword(s):  
Virus Infection ◽  
Pregnant Women ◽  
Zika Virus ◽  
Zika Virus Infection

scholarly journals Human Monoclonal Antibodies as Adjuvant Treatment of Chronic Hepatitis B Virus Infection

2019 ◽  
Vol 10 ◽  
Author(s):  
Antonella Cerino ◽  
Stefania Mantovani ◽  
Dalila Mele ◽  
Barbara Oliviero ◽  
Stefania Varchetta ◽  
...  
Keyword(s):  
Chronic Hepatitis ◽  
Monoclonal Antibodies ◽  
Hepatitis B Virus ◽  
Virus Infection ◽  
Hepatitis B ◽  
Adjuvant Treatment ◽  
Hepatitis B Virus Infection ◽  
Human Monoclonal Antibodies ◽  
Chronic Hepatitis B Virus ◽  
B Virus

scholarly journals Autophagy Contributes to Host Immunity and Protection against Zika Virus Infection via Type I IFN Signaling

2020 ◽  
Vol 2020 ◽  
pp. 1-15 ◽  
Author(s):  
Yuyi Huang ◽  
Yujie Wang ◽  
Shuhui Meng ◽  
Zhuohang Chen ◽  
Haifan Kong ◽  
...  
Keyword(s):  
Virus Infection ◽  
Cell Line ◽  
Zika Virus ◽  
Fetal Brain ◽  
Host Immunity ◽  
Type I ◽  
Type I Ifn ◽  
Zikv Infection

Recent studies have indicated that the Zika virus (ZIKV) has a significant impact on the fetal brain, and autophagy is contributing to host immune response and defense against virus infection. Here, we demonstrate that ZIKV infection triggered increased LC3 punctuation in mouse monocyte-macrophage cell line (RAW264.7), mouse microglial cell line (BV2), and hindbrain tissues, proving the occurrence of autophagy both in vitro and in vivo. Interestingly, manual intervention of autophagy, like deficiency inhibited by 3-MA, can reduce viral clearance in RAW264.7 cells upon ZIKV infection. Besides, specific siRNA strategy confirmed that autophagy can be activated through Atg7-Atg5 and type I IFN signaling pathway upon ZIKV infection, while knocking down of Atg7 and Atg5 effectively decreased the ZIKV clearance in phagocytes. Furthermore, we analyzed that type I IFN signaling could contribute to autophagic clearance of invaded ZIKV in phagocytes. Taken together, our findings demonstrate that ZIKV-induced autophagy is favorable to activate host immunity, particularly through type I IFN signaling, which participates in host protection and defense against ZIKV infection.

scholarly journals Atovaquone Inhibits Arbovirus Replication through the Depletion of Intracellular Nucleotides

2019 ◽  
Vol 93 (11) ◽  
Author(s):  
Angelica Cifuentes Kottkamp ◽  
Elfie De Jesus ◽  
Rebecca Grande ◽  
Julia A. Brown ◽  
Adam R. Jacobs ◽  
...  
Keyword(s):  
Viral Replication ◽  
Pregnant Women ◽  
Vulnerable Populations ◽  
Zika Virus ◽  
Ex Vivo ◽  
Pyrimidine Biosynthesis ◽  
Zikv Infection ◽  
Antiviral Therapies ◽  
Virion Production ◽  
Women And Children

ABSTRACT Arthropod-borne viruses represent a significant public health threat worldwide, yet there are few antiviral therapies or prophylaxes targeting these pathogens. In particular, the development of novel antivirals for high-risk populations such as pregnant women is essential to prevent devastating disease such as that which was experienced with the recent outbreak of Zika virus (ZIKV) in the Americas. One potential avenue to identify new and pregnancy-acceptable antiviral compounds is to repurpose well-known and widely used FDA-approved drugs. In this study, we addressed the antiviral role of atovaquone, an FDA Pregnancy Category C drug and pyrimidine biosynthesis inhibitor used for the prevention and treatment of parasitic infections. We found that atovaquone was able to inhibit ZIKV and chikungunya virus virion production in human cells and that this antiviral effect occurred early during infection at the initial steps of viral RNA replication. Moreover, we were able to complement viral replication and virion production with the addition of exogenous pyrimidine nucleosides, indicating that atovaquone functions through the inhibition of the pyrimidine biosynthesis pathway to inhibit viral replication. Finally, using an ex vivo human placental tissue model, we found that atovaquone could limit ZIKV infection in a dose-dependent manner, providing evidence that atovaquone may function as an antiviral in humans. Taken together, these studies suggest that atovaquone could be a broad-spectrum antiviral drug and a potential attractive candidate for the prophylaxis or treatment of arbovirus infection in vulnerable populations, such as pregnant women and children. IMPORTANCE The ability to protect vulnerable populations such as pregnant women and children from Zika virus and other arbovirus infections is essential to preventing the devastating complications induced by these viruses. One class of antiviral therapies may lie in known pregnancy-acceptable drugs that have the potential to mitigate arbovirus infections and disease, yet this has not been explored in detail. In this study, we show that the common antiparasitic drug atovaquone inhibits arbovirus replication through intracellular nucleotide depletion and can impair ZIKV infection in an ex vivo human placental explant model. Our study provides a novel function for atovaquone and highlights that the rediscovery of pregnancy-acceptable drugs with potential antiviral effects can be the key to better addressing the immediate need for treating viral infections and preventing potential birth complications and future disease.

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