Biology subjects

Shiakolas, A.

Publications and source records attributed to Shiakolas, A..

3 recordsLinked to original sources

bioRxiv2024

Discovery and Characterization of a Pan-betacoronavirus S2-binding antibody

SUMMARY/ABSTRACTThree coronaviruses have spilled over from animal reservoirs into the human population and caused deadly epidemics or pandemics. The continued emergence of coronaviruses highlights the need for pan-coronavirus interventions for effective pandemic preparedness. Here, using LIBRA-seq, we report a panel of 50 coronavirus antibodies isolated from human B cells. Of these antibodies, 54043-5 was shown to bind the S2 subunit of spike proteins from alpha-, beta-, and deltacoronaviruses. A cryo-EM structure of 54043-5 bound to the pre-fusion S2 subunit of the SARS-CoV-2 spike defined an epitope at the apex of S2 that is highly conserved among betacoronaviruses. Although non-neutralizing, 54043-5 induced Fc-dependent antiviral responses, including ADCC and ADCP. In murine SARS-CoV-2 challenge studies, protection against disease was observed after introduction of Leu234Ala, Leu235Ala, and Pro329Gly (LALA-PG) substitutions in the Fc region of 54043-5. Together, these data provide new insights into the protective mechanisms of non-neutralizing antibodies and define a broadly conserved epitope within the S2 subunit.

molecular biology↗

bioRxiv2022

An antibody targeting the N-terminal domain of SARS-CoV-2 disrupts the spike trimer

The protective human antibody response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus focuses on the spike (S) protein which decorates the virion surface and mediates cell binding and entry. Most SARS-CoV-2 protective antibodies target the receptor- binding domain or a single dominant epitope ( supersite) on the N terminal domain (NTD). Here, using the single B cell technology LIBRA-seq, we isolated a large panel of NTD-reactive and SARS-CoV-2 neutralizing antibodies from an individual who had recovered from COVID-19. We found that neutralizing antibodies to the NTD supersite commonly are encoded by the IGHV1-24 gene, forming a genetic cluster that represents a public B cell clonotype. However, we also discovered a rare human antibody, COV2-3434, that recognizes a site of vulnerability on the SARS-CoV-2 S protein in the trimer interface and possesses a distinct class of functional activity. COV2-3434 disrupted the integrity of S protein trimers, inhibited cell-to-cell spread of virus in culture, and conferred protection in human ACE2 transgenic mice against SARS-CoV-2 challenge. This study provides insight about antibody targeting of the S protein trimer interface region, suggesting this region may be a site of virus vulnerability.

immunology↗

bioRxiv2018

Accurate Prediction of Antibody Resistance in Clinical HIV-1 Isolates

Broadly neutralizing antibodies (bNAbs) targeting the HIV-1 envelope glycoprotein (Env) have promising utility in prevention and treatment of HIV-1 infection with several undergoing clinical trials. Due to high sequence diversity and mutation rate of HIV-1, viral isolates are often resistant to particular bNAbs. Resistant strains are commonly identified by time-consuming and expensive in vitro neutralization experiments. Here, we developed machine learning-based classifiers that accurately predict resistance of HIV-1 strains to 33 neutralizing antibodies. Notably, our classifiers achieved an overall prediction accuracy of 96% for 212 clinical isolates from patients enrolled in four different clinical trials. Moreover, use of the tree-based machine learning method gradient boosting machine enabled us to identify critical epitope features that distinguish between antibody resistance and sensitivity. The availability of an in silico antibody resistance predictor will facilitate informed decisions of antibody usage in clinical settings.

bioinformatics↗