Structural and molecular contributions to the understanding of antibody recognition of pathogenic viruses

Viral infections can have huge global impacts, as evidenced by the recent 2019 coronavirus disease pandemic (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). History contains many other examples, such as the Ebola epidemics of 2013-2016, the H1N1 pandemic of 2009-2010, etc. Structural biology aims to determine how antibodies induced during infection or vaccination target viral proteins. A new review published in Virus examines how molecular and structural biology has contributed to our understanding of the recognition of antibodies to HIV-1, SARS-CoV-2 and Zika.

To study: How antibodies recognize pathogenic viruses: structural correlates of neutralization of HIV-1, SARS-CoV-2 and Zika antibodies. Image Credit: Fotomay / Shutterstock

A mThat one sThis way

SARS-CoV, Middle East Respiratory Syndrome (MERS), Acquired Immune Deficiency Syndrome (AIDS), Zika virus (ZIKV) and SARS-CoV- 2. The rapid development of vaccines and safe treatments and efficacy has been shown to be essential in reducing morbidity and mortality from emerging viruses.

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

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

Human immunodeficiency virus 1 (HIV-1) is responsible for the AIDS pandemic and has long posed a challenge for vaccine development due to its striking ability to evade host immune responses. It contains a single viral protein (Envelope or Env) which facilitates infection. Advances in X-ray crystallography and cryo-EM have made it possible to structurally characterize broadly neutralizing antibodies (bNAb) interactions with Env and Env conformational changes that subsequently informed vaccine design.

The spike (S) proteins on the surface of SARS-CoV-2 allow it to infect host cells. Structural biology has been instrumental in the rapid characterization and evaluation of S protein and antibodies produced during natural infection. It has saved countless lives by contributing to the development of COVID-19 vaccines and monoclonal Ab (mAb) therapies.

ZIKV is a mosquito-borne virus that can cause microcephaly and neurodevelopmental abnormalities in newborns of infected mothers. There is not yet a safe and effective vaccine against ZIKV that is universally available.

Main Fclues

Structural analysis identified neutralizing epitopes on HIV-1, SARS-CoV-2 and ZIKV. X-ray crystallography and cryo-EM analyzes of the virus have made it possible to better understand the mechanisms of neutralization by Abs and to identify new therapeutic targets. In the case of HIV-1, bNAbs targets can be divided into several categories, each presenting a distinct landscape for bNAbs binding and posing different challenges for Abs to overcome. The mode of binding of bNAbs to all epitopes has been demonstrated in structural biology.

The X-ray and cryo-EM crystallographic structures of Ab: Env complexes are essential to characterize the binding mode of bNAbs and to understand the context of atypical features. These data have assisted in the structure-based design of gp120 and SOSIP-based immunogens, which elicit responses to particular epitopes and design small molecule drugs.

In the case of SARS-CoV-2, the S protein consists of three identical subunits, each containing an RBD. Antibodies that recognize RBD are a vital part of the neutralizing Ab response. While scientists have primarily focused on RBD, an increasing number of neutralizing Abs that target other regions of the S protein have been found (eg, the NTD and S2 domains). In addition, some of these Abs are also largely cross-reactive with other beta-coronaviruses.

ZIKV protein E is essential for facilitating cell entry and fusion, making it an important target of nAbs that effectively eliminate ZIKV. Structural characterization of Abs that bind to ZIKV E protein revealed multiple epitopes. Some Ab epitopes (characterized by crystallography) are not accessible on known cryo-EM structures of mature ZIKV, as evidence suggests that E proteins are dynamic and sample different conformations. It should be noted that the phenomenon of “respiration” of flaviviruses may be the result of changes in the conformation of protein E during the viral life cycle. However, the respiratory conformation of ZIKV has not yet been determined.

Figure 1: Ab characterization scheme and therapeutic development. Ab binding epitopes isolated from infected or vaccinated individuals or animal studies are determined by structural analysis of Fab-viral antigen complexes. These structures inform the design of vaccines, monoclonal antibodies and small molecule therapeutics that can be tested in clinical trials and animal models. Surface representations are shown for the following structures: Fab — SARS-CoV-2S (PDB 7K90), Fab — ZIKV EDIII (PDB 5VIG), Fab — HIV-1 Env (PDB 5T3Z) and small molecule inhibitor — HIV -1 Approx (PDB 7LO6).

Conclusion

Structural biology has provided insight into immune responses to viruses, such as HIV-1, SARS-CoV-2, and ZIKV. The structures of Abs bound to viral proteins have increased our understanding of the role of characteristics that Abs develop in response to antigens. Using structural and molecular biology methods, scientists have made huge strides towards anti-Ab treatments and vaccines for the HIV-1, SARS-CoV-2, and ZIKV viruses.