Structural and molecular contributions to understanding antibody recognition of pathogenic viruses

Viral infections can have significant global consequences, as evidenced by the recent pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). There is a sex. There are many other examples in history, such as the 2013-2016 Ebola epidemic and the 2009-2010 H1N1 pandemic. Structural biology aims to determine how antibodies induced during infection or vaccination target viral proteins.New review published in virus We will review how molecular and structural biology contributed to the understanding of HIV-1, SARS-CoV-2, and Zika antibody recognition.

study: How Antibodies Recognize Pathogenic Viruses: Structural Correlation of Antibody Neutralizing of HIV-1, SARS-CoV-2, and Zika.. Image Credit: Fotomay / Shutterstock

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Examples of viruses that have caused global turmoil and required urgent development of vaccines and treatments are SARS-CoV, Middle East Respiratory Syndrome (MERS), Acquired Immune Deficiency Syndrome (AIDS), and ZIKV. ), And the current SARS-CoV-. 2.2. The rapid development of safe and effective vaccines and treatments has proven essential to reducing morbidity and mortality from emerging viruses.

Structural biologists are continually advancing X-ray crystallography and cryo-electron microscopy (cryo-EM) techniques to investigate viruses and viral proteins. In this study, scientists investigated viral antibody (Ab) recognition by elucidating the 3D structure of viral proteins bound to Abs induced by infection or vaccination. This is essential for the development of effective monoclonal antibody therapies and vaccines.

HIV-1, SARS-CoV-2, and Zika virus

Human immunodeficiency virus 1 (HIV-1) is responsible for the AIDS pandemic and has long challenged vaccine development due to its amazing ability to evade the host’s immune response. Contains a single viral protein (envelope or Env) that promotes infection. Advances in X-ray crystallography and cryo-EM have made it possible to broadly characterize structures. Neutralizing antibody (BNAb) Env and its interaction with conformational change then inform vaccine design.

The spike (S) protein on the surface of SARS-CoV-2 allows infection of host cells. Structural biology has helped to quickly characterize and evaluate S proteins and antibodies produced by natural infections. It has saved countless lives by contributing to the development of COVID-19 vaccines and monoclonal antibody (mAb) therapeutics.

ZIKV is a mosquito-borne virus that can cause microcephaly and neurodevelopmental disorders in newborns of infected mothers. There is still no safe and effective vaccine against ZIKV that is universally available.

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Structural analysis helped identify neutralizing epitopes for HIV-1, SARS-CoV-2, and ZIKV. Both viral X-ray crystallography and cryo-electron microscopy provided insights into the mechanism of neutralization by Abs and identified new therapeutic targets. In the case of HIV-1, bNAb targets can be divided into multiple categories, each of which presents a clear status of bNAb binding and poses various challenges for Abs to overcome. The binding mode of bNAb at all epitopes is emphasized in structural biology.

The X-ray crystal structure and cryo-EM structure of the Ab: Env complex characterize the binding mode of bNAb and are key to understanding the context of atypical features. These data helped in the structure-based design of gp120 and SOSIP-based immunogens. These elicit a response to a particular epitope and design small molecule drugs.

For SARS-CoV-2, the S protein contains three identical subunits, each containing an RBD. Antibodies that recognize RBD are an important part of the neutralizing antibody response. Scientists are primarily focused on RBD, but an increasing number of neutralizing antibodies target other regions of the S protein, such as the NTD and S2 domains. In addition, some of these abdominal muscles also cross-react broadly with other betacoronaviruses.

The ZIKV E protein is the key to facilitating cell invasion and fusion and is an important target for nAb to effectively eliminate ZIKV. The structural features of the antibody that binds to the ZIKV E protein revealed multiple epitopes. Some Ab epitopes (characterized by crystallography) are not accessible in the known cryo-EM structure of mature ZIKV, as evidence suggests that the E protein is dynamic and samples different conformations. .. It should be noted that the flavivirus “breathing” phenomenon may be the result of conformational changes in the E protein during the viral life cycle. However, the respiratory conformation of ZIKV has not yet been determined.

Figure 1: Schematic diagram of Ab characterization and treatment development. The binding epitopes of Abs isolated from infected or vaccinated individual or animal studies are determined by structural analysis of the Fab-viral antigen complex. These structures provide information for the design of vaccines, monoclonal antibodies, and small molecule therapeutics that can be tested in clinical trials and animal models. The surface representation of the structure is shown: Fab-SARS-CoV-2 S (PDB 7K90), Fab-ZIKV EDIII (PDB 5VIG), Fab-HIV-1 Env (PDB 5T3Z), and small molecule inhibitors -HIV-1 environment (PDB 7LO6).

Conclusion

Structural biology has given us a better understanding of the immune response to viruses such as HIV-1, SARS-CoV-2, and ZIKV. The structure of Abs bound to viral proteins has provided a better understanding of the role of functions that Abs develops in response to antigens. Scientists have made great strides towards Ab treatment and vaccines for the HIV-1, SARS-CoV-2, and ZIKV viruses using structural and molecular biology techniques.