Mahek Sharan, Institute of Applied Medicines and Research, Ghaziabad
A Nanobody has been developed by a small fragment of the antibody of a llama. This Nanobody has the capability to chase and enabling the immune cells to find and kill HCMV.
What is Human cytomegalovirus (HCMV)?
Cytomegalovirus is a virus that infects monkeys and humans. The virus comes under the Herpesviridae family and includes 11 species of virus belonging to this genus. HCMV (Human betaherpesvirus-5) is among one of the 11 species that infect humans. There are several diseases associated with Human CMV which is the most studied virus of all cytomegaloviruses. HCMV is an enveloped virus with geometry ranging from icosahedral to spherical and T-16 symmetry. The non-segmented and linear genome of 200kb is carried by this virus of 150-200nm in length.
Figure 1 HCMV structure
The replication of this virus is lysogenic and happens in the nucleus. HCMV attaches from glycoproteins to the receptor of the host. HCMV follows the dsDNA bidirectional model of replication followed by transcription and leaky scanning translation. This virus is transmitted by the fluids of the body like saliva, genital secretions, and urine from an infected human to others. CD34 progenitor cells and CD14 monocytes are the sites for the latent infection of HCMV.
In the United Kingdom, the data suggests that around four out of five people are infected with HCMV and the data of infection in the developed countries could be as high as 95%. The virus has the ability to hide inside the WBCs in the dormant state. This results in the long window period of decades to remain undetected and undisturbed in the host body. Although the virus reinfection does not cause any symptoms in a healthy individual but causes devastating effects in immunocompromised patients. Immunocompromised patients are the ones who are under immunosuppressant medication to avoid organ rejection after an organ transplant. The infection of HCMV in these patients is lethal as there is no specific vaccine available and the anti-viral drugs show serious side effects.
What are nanobodies?
Human antibodies comprise 2 light and 2 heavy chains that work in a combined form to recognize and attach to the surface of viruses or cells. Nanobody is another name of single-domain antibody (sdAb) which is a fragment of an antibody that consists of a single monomeric variable domain. Camelids is a family that includes animals like alpacas, llamas, and dromedary, along with camels are known to be the first category of animals to have Nanobodies. These Nanobodies of camelids contain only a single fragment of antibody but are sufficient for antigen recognition.
Figure 2 Llama nanobody that comprises of heavy chain only
The methodology of current research
US28-targeting nanobody VUN100 was used to develop a new bivalent format VUN100bv. The UK and the Netherlands team has been able to develop nanobodies that are designed to target US28, which is a specific virus protein. At the surface of the latent HCMV infected cell has US28 on its surface and acts as the main driver of this latent state. In the experiment, HCMV infected blood sample was taken that showed successful binding of nanobody to US28 protein. Along with this, it was able to interrupt the signals that were caused by the protein to keep HCMV in a dormant state. When the nanobody exposes the virus then the immune cells of the host was able to detect the infection and kill the virus that leads to blood clearance.
The 2 antagonistic monovalent VUN100 nanobodies are conjoined to form a partial inverse agonistic property bivalent format. The study about the mechanism of this process is still under observation but is known to show a similar mechanism like chemokine targeting receptors. The mechanism of the process is known as the shock and kill strategy. In CD14 monocytes, upregulation of expression of IE gene without the late gene expression, reactivation of the virus, and viral DNA replication were observed. VUN100 in THP-1 cells was also able to restore the IFI16 levels partially with IE gene expression induction in CD14 cells. Whereas VUN100bv is observed to robustly induce IE expression in infected hosts leading to killing by CTLs. The nanobody efficiency in clinical along with experimental settings could be improved if it is coupled to an effector molecule.
Current Research
In the current research featured in Nature Communications that was conducted by Dr. Timo W.M De Groof and his colleagues at Vrije Universiteit Amsterdam and the University of Cambridge, a Nanobody has been developed to hunt the virus from its dormant state. A special type of Nanobody has been developed from llama to eradicate HCMV from its hiding place. This leads to the immune cells finding out and destroying this deadly virus from the immunocompromised patients. The first author of this research project, Dr. Timo W.M De Groof said that as compared to antibodies, nanobodies are small, this feature ensures the perfect suitability for specific antigens. He added that nanobodies are relatively easier to manufacture. He showed hope for nanobodies to revolutionize the therapy related to antibodies.
Ablynx is a company of biopharmaceuticals that in the market has introduced one of the first approved nanobodies. There are still nanobodies for other diseases like cancer and rheumatoid arthritis under the clinical trial. This could lead to lower mortality and incidence of diseases associated with CMV during stem cell transplantation and organ transplant.
Also read: Pomegranate compound Punicalagin for Cancer prevention
References
- De Groof, T. W. M., Elder, E. G., Lim, E. Y., Heukers, R., Bergkamp, N. D., Groves, I. J., Wills, M., Sinclair, J. H., & Smit, M. J. (2021). Targeting the latent human cytomegalovirus reservoir for T-cell-mediated killing with virus-specific nanobodies. Nature Communications, 12(1), 4436. https://doi.org/10.1038/s41467-021-24608-5
- Cambridge, U. of. (n.d.). Llama “nanobodies” could hold key to preventing deadly post-transplant infection. Retrieved August 5, 2021, from https://phys.org/news/2021-07-llama-nanobodies-key-deadly-post-transplant.html
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Author’s Info:
Mahek Sharan is an MTech (Biotechnology) student who aspires to become a researcher with the enthusiasm to learn and explore more in molecular research.
LinkedIn: https://www.linkedin.com/in/mahek-sharan-601474152
Publications:
1. https://sciensage.info/current_issue_publish.php?p=948
2. https://bioingene.com/wp-content/uploads/2021/06/D28MLY20R16.pdf
3. https://drive.google.com/file/d/1ep4AfEKM3GV61fzmvRvTnlRafG3kueFL/view
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