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In vivo time-related evaluation of a therapeutic neutralization monoclonal antibody against lethal enterovirus 71 infection in a mouse model.

ABSTRACT: Enterovirus 71 (EV71) is a neurotropic virus capable of inducing severe neurological symptoms and death. No direct targeting antivirals are useful in the treatment of severe EV71 infection. Because of low toxicity and good specificity, monoclonal antibodies (MAb) are a potential candidate for the treatment of viral infections. Therefore, we developed an EV71-specific conformational MAb with high in vitro cross-neutralization activity to heterologous EV71 subgenotypes. The in vivo treatment experiment at different days post-infection indicated that a single treatment of MAb CT11F9 within day 3 post-infection fully protected mice from morbidity and mortality (0% PBS vs. 100% at 10 µg/g per body weight ***P<0.0001). Immunohistochemical and histological analysis confirmed that CT11F9 significantly prohibited EV71 VP1 expression in various tissues and prevented EV71-induced myonecrosis. Moreover, thrice-treatment at day 4, 5, 6 post-infection was associated with an increased survival rate (18.2% single vs. 50% thrice at 20 µg/g per body weight), and the mice recovered from limb paralysis. Competitive ELISA also confirmed that CT11F9-recognized epitopes were immunodominant in humans. In conclusion, MAb CT11F9 is an ideal candidate to be humanized and used in severe EV71 infection.

SUBMITTER: Li Z

PROVIDER: S-EPMC4184856 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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In vivo time-related evaluation of a therapeutic neutralization monoclonal antibody against lethal enterovirus 71 infection in a mouse model.

Li Zhiqun Z Xu Longfa L He Delei D Yang Lisheng L Liu Che C Chen Yixin Y Shih James Wai Kuo JW Zhang Jun J Zhao Qinjian Q Cheng Tong T Xia Ningshao N

PloS one 20141003 10

Enterovirus 71 (EV71) is a neurotropic virus capable of inducing severe neurological symptoms and death. No direct targeting antivirals are useful in the treatment of severe EV71 infection. Because of low toxicity and good specificity, monoclonal antibodies (MAb) are a potential candidate for the treatment of viral infections. Therefore, we developed an EV71-specific conformational MAb with high in vitro cross-neutralization activity to heterologous EV71 subgenotypes. The in vivo treatment exper ...[more]

PMID: 25279734

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Project description:Despite significant advances in health care, outbreaks of infections by enteroviruses (EVs) continue to plague the Asia-Pacific region every year. Enterovirus 71 (EV71) causes hand-foot-and-mouth disease (HFMD), for which there are currently no therapeutics. Here, we report two new antibodies, A9 and D6, that potently neutralize EV71. A9 exhibited a 50% neutralizing concentration (neut50) value of 0.1 nM against EV71, which was 10-fold lower than that observed for D6. Investigation into the mechanisms of neutralization revealed that binding of A9 to EV71 blocks receptor binding but also destabilizes and damages the virus capsid structure. In contrast, D6 destabilizes the capsid only slightly but interferes more potently with the attachment of the virus to the host cells. Cryo-electron microscopy (cryo-EM) structures of A9 and D6 bound with EV71 shed light on the locations and nature of the epitopes recognized by the two antibodies. Although some regions of the epitopes recognized by the two antibodies overlap, there are differences that give rise to dissimilarities in potency as well as in the mechanisms of neutralization. Interestingly, the overlapping regions of the epitopes encompass the site that the virus uses to bind SCARB2, explaining the reason for the observed blocking of the virus-receptor interaction by the two antibodies. We also identified structural elements that might play roles in modulating the stability of the EV71 particles, including particle integrity. The molecular features of the A9 and D6 epitopes unveiled in this study open up new avenues for rationally designing antiviral drugs.IMPORTANCE During the course of viral infections, the human body produces neutralizing antibodies which play a defining role in clearing the virus. From this study, we report two new, highly potent neutralizing antibodies, A9 and D6, against enterovirus 71 (EV71), the causative agent of HFMD. Both antibodies prevent the virus from entering the host cell, a step that is important for establishing a successful infection. A9 destabilizes and damages the virus capsid that forms an outer protective covering around the genome of the virus, while also interfering with virus attachment to the host cells. In contrast, D6 only prevents binding of the virus to its receptor(s). The mechanism of neutralization of A9 is unique and has not been observed before for neutralizing antibodies targeting EVs. The two antibodies that we are reporting in this study have potential to be developed into much-needed therapeutic interventions for treatment of HFMD, outbreaks of which are reported every year in the Asia-Pacific region.

Dataset Information

In vivo time-related evaluation of a therapeutic neutralization monoclonal antibody against lethal enterovirus 71 infection in a mouse model.

Publications

In vivo time-related evaluation of a therapeutic neutralization monoclonal antibody against lethal enterovirus 71 infection in a mouse model.

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