Understanding how Zika virus interacts with human antibody C10 paves way for new therapeutic target

As Zika virus spreads throughout the world, the call for rapid development of therapeutics to treat Zika virus rings loud and clear. Taking a step further in identifying a possible therapeutic candidate, a team of researchers at Duke-NUS Medical School (Duke-NUS), in collaboration with scientists from the University of North Carolina, have discovered the mechanism by which C10, a human antibody previously identified to react with the Dengue virus, prevents Zika virus infection at a cellular level.

C10 antibody (purple) visualized to be interacting with
the Zika virus coat (green). Credit:Victor Kostyuchenko,
Duke-NUS Medical School
Previously, C10 was identified as one of the most potent antibodies able to neutralize Zika virus infection. Now, Associate Prof Lok Shee-Mei and her team at the Emerging Infectious Disease Programme of Duke-NUS have taken it one step further by determining how C10 is able to prevent Zika virus infection.
To infect a cell, virus particles usually undergo two main steps, docking and fusion, which are also common targets for disruption when developing viral therapeutics. During docking, the virus particle identifies specific sites on the cell and binds to them. With Zika virus infection, docking then initiates the cell to take the virus in via an endosome – a separate compartment within the cell body. Proteins within the virus coat undergo structural changes to fuse with the membrane of the endosome, thereby releasing the virus genome into the cell, and completing the fusion step of infection.

Using a method called cryoelectron microscopy, which allows for the visualization of extremely small particles and their interactions, the team visualized C10 interacting with the Zika virus under different pHs, so as to mimic the different environments both the antibody and virus will find themselves in throughout infection. They showed that C10 binds to the main protein that makes up the Zika virus coat, regardless of pH, and locks these proteins into place, preventing the structural changes required for the fusion step of infection. Without fusion of the virus to the endosome, viral DNA is prevented from entering the cell, and infection is thwarted.

“Hopefully, these results will further accelerate the development of C10 as a Zika virus therapy to combat its effects of microcephaly and Guillain-Barré syndrome. This should emphasise the need for further studies of the effect of C10 on Zika virus infection in animal models,” commented Dr Lok.

“By defining the structural basis for neutralization, these studies provide further support for the idea that this antibody will protect against Zika virus infection, potentially leading to a new therapy to treat this dreaded disease,” says Ralph Baric, PhD, professor in the Department of Epidemiology at UNC’s Gillings School of Global Public Health.

These findings suggest that C10 may be developed as a therapy for Zika virus infection, and should be further explored. In addition, disrupting fusion with C10 may prove to be more effective in preventing Zika virus infection compared with therapies that attempt to disrupt docking. This is because the fusion step is critical for Zika virus infection, while the virus may develop other mechanisms to overcome disruptions to the docking step. With the call for rapid development of Zika therapies, C10 has emerged as a front runner to answer this call.

Citation: “Neutralization mechanism of a highly potent antibody against Zika virus”. Shuijun Zhang, Victor A. Kostyuchenko, Thiam-Seng Ng, Xin-Ni Lim, Justin S. G. Ooi, Sebastian Lambert, Ter Yong Tan, Douglas G. Widman, Jian Shi, Ralph S. Baric & Shee-Mei Lok. Nature Communications 2016 vol: 7 pp: 13679.
DOI: 10.1038/ncomms13679
Research funding: Singapore Ministry of Education, National Research Foundation, Singapore Ministry of Health, National Institutes of Health.
Adapted from press release by Duke-NUS Medical School.

Mathematical model suggests increase in Zika virus outbreaks following Dengue fever vaccination

Vaccinating against dengue fever could increase outbreaks of Zika, suggests new research out of York University and Xi’an Jiaotong University in China. The research identifies a potentially serious public health concern. More than a third of the world’s population lives in areas where dengue is endemic and cases of co-infection with Zika have already been reported.

Conducted at York University’s Laboratory for Industrial and Applied Mathematics using mathematical modelling, the research was led by Biao Tang, an exchange PhD student from Xi’an Jiaotong University, in collaboration with York Professor Jianhong Wu and Tang’s supervisor, Professor Yanni Xiao at Xi’an Jiaotong University. As dengue and Zika are both part of the Flaviviridae family transmitted through a common mosquito host, the researchers wanted to know how vaccinating for one would affect the incidence of the other.

“Vaccinating against one virus could not only affect the control of another virus, it could in fact make it easier for the other to spread,” says Wu. “Recent evidence suggests that dengue virus antibodies can enhance the Zika virus infection. For that reason, we developed a new math model to investigate the effect of dengue vaccination on Zika outbreaks.”  The paper, “Implication of vaccination against dengue for Zika outbreak,” was published in Scientific Reports.

The team’s model shows that vaccinations for dengue increase the number of people contracting Zika. It also shows that the more people in a particular population that are vaccinated against dengue, the earlier and larger the Zika outbreak. The research also found that the most effective way to minimize the unintended effect of dengue vaccinations on Zika outbreaks is through an integrated strategy that includes mosquito control.

The researchers note their findings do not discourage the development and promotion of dengue vaccine products, however, more work needs to be done to understand how to optimize dengue vaccination programs and minimize the risk of Zika outbreaks.

Citation: Tang, Biao, Yanni Xiao, and Jianhong Wu. “Implication of vaccination against dengue for Zika outbreak.” Scientific Reports 6 (2016).
DOI: http://dx.doi.org/10.1038/srep35623
Adapted from press release by York University and Xi’an Jiaotong University

Zika virus evolution and spread

In a study published in Pathogens and Global Health, researchers have modelled the evolutionary development and diversity of the Zika virus to better understand how infection spreads between populations and how the virus reacts with the immune system. Such an understanding is essential if an effective vaccine is to be developed.

First found in Uganda in 1947, Zika is the newest discovery among a group of mosquito-transmitted viruses known as flaviviruses. It is an emerging threat in South and Central America and the Caribbean, with the recent Brazilian epidemic resulting in 440,000-1,300,000 cases and spreading to more than thirteen other countries.

While infected people usually show no symptoms, these can include fever, rash, joint pain or conjunctivitis. In addition, the Brazilian outbreak indicated Zika might cause fetal losses in pregnant women or microcephaly in infants born to infected women.

Dr. Silvia Angeletti from the University Campus Bio-Medico, Rome, and colleagues, carried out evolutionary analysis of the virus combined with homology (shared ancestry) modelling and T- and B-cells epitope prediction, which aims to determine how immune system responses cause the virus to react and change.

Their analysis revealed two distinct genotypes of the virus, African and Asiatic, and two separate clades (biological groupings that include a common ancestor and all the descendants of that ancestor). Clade I represented African gene sequences and Clade II, sequences of Asiatic and Brazilian origin.

The Brazilian sequences were found to be closely related to a sequence from French Polynesia. This lends support to the hypothesis that the virus might have been introduced to Brazil during the Va’a World Sprint Canoeing Championship in Rio de Janeiro in 2014, which included a team from French Polynesia, rather than the World Cup in which no teams from Pacific countries participated.

Among the factors that influence Zika infection, ‘antigenic variability’ (the way the virus alters its surface proteins to evade the host’s immune response) and pre-existing immunity caused by cross-reactions with other viruses might play an important role. Such cross-reactions also make diagnosis of Zika infection unreliable, and could thus facilitate the spread of the virus.

“Understanding the differences and similarities between Zika and other flaviviruses, such as the dengue fever and chikungunya viruses, is essential if effective drugs, vaccines and Zika-specific immunological tests for large population screening are to be designed,” the authors say.

Adapted from press release by Taylor & Francis