ORCID Profile
0000-0002-5295-9067
Current Organisation
Hong Kong University of Science and Technology
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Communications engineering | Signal processing | Wireless communication systems and technologies (incl. microwave and millimetrewave) |
Publisher: Springer Science and Business Media LLC
Date: 17-06-2020
Publisher: Cold Spring Harbor Laboratory
Date: 14-12-2021
DOI: 10.1101/2021.12.12.472315
Abstract: Omicron, the most recent SARS-CoV-2 variant of concern (VOC), harbours multiple mutations in the spike protein that were not observed in previous VOCs. Initial studies suggest Omicron to substantially reduce the neutralizing capability of antibodies induced from vaccines and previous infection. However, its effect on T cell responses remains to be determined. Here, we assess the effect of Omicron mutations on known T cell epitopes and report data suggesting T cell responses to remain broadly robust against this new variant.
Publisher: Research Square Platform LLC
Date: 27-01-2023
DOI: 10.21203/RS.3.RS-2487027/V1
Abstract: Direct-acting antiviral agents (DAAs) provide efficacious therapeutic treatments for chronic Hepatitis C virus (HCV) infection. However, emergence of drug resistance mutations (DRMs) can greatly affect treatment outcomes and impede virological cure. While multiple DRMs have been observed for all currently used DAAs, the evolutionary determinants of such mutations are not currently well understood. Here, by considering DAAs targeting the nonstructural 3 (NS3) protein of HCV, we present results suggesting that epistasis plays an important role in the evolution of DRMs. Using a sequence-based fitness landscape model that we validate using experimental data, we identify specific DRMs that are associated with strong epistatic interactions, and these are found to be enriched in multiple NS3-specific DAAs. We further demonstrate, using evolutionary modelling, that the identified DRMs involve compensatory mutational interactions that facilitate relatively easy escape from drug-induced selection pressures. Our results indicate that accounting for epistasis is important for designing future HCV NS3-targeting DAAs.
Publisher: Oxford University Press (OUP)
Date: 04-12-2019
DOI: 10.1093/BIOINFORMATICS/BTZ890
Abstract: Patterns of mutational correlations, learnt from protein sequences, have been shown to be informative of co-evolutionary sectors that are tightly linked to functional and/or structural properties of proteins. Previously, we developed a statistical inference method, robust co-evolutionary analysis (RoCA), to reliably predict co-evolutionary sectors of proteins, while controlling for statistical errors caused by limited data. RoCA was demonstrated on multiple viral proteins, with the inferred sectors showing close correspondences with experimentally-known biochemical domains. To facilitate seamless use of RoCA and promote more widespread application to protein data, here we present a standalone cross-platform package ‘RocaSec’ which features an easy-to-use GUI. The package only requires the multiple sequence alignment of a protein for inferring the co-evolutionary sectors. In addition, when information on the protein biochemical domains is provided, RocaSec returns the corresponding statistical association between the inferred sectors and biochemical domains. The RocaSec software is publicly available under the MIT License at hmedaq/RocaSec. Supplementary data are available at Bioinformatics online.
Publisher: MDPI AG
Date: 03-09-2022
DOI: 10.3390/V14091960
Abstract: Beginning in May 2022, a novel cluster of monkeypox virus infections was detected in humans. This virus has spread rapidly to non-endemic countries, sparking global concern. Specific vaccines based on the vaccinia virus (VACV) have demonstrated high efficacy against monkeypox viruses in the past and are considered an important outbreak control measure. Viruses observed in the current outbreak carry distinct genetic variations that have the potential to affect vaccine-induced immune recognition. Here, by investigating genetic variation with respect to orthologous immunogenic vaccinia-virus proteins, we report data that anticipates immune responses induced by VACV-based vaccines, including the currently available MVA-BN and ACAM2000 vaccines, to remain highly cross-reactive against the newly observed monkeypox viruses.
Publisher: Cold Spring Harbor Laboratory
Date: 25-04-2018
DOI: 10.1101/307033
Abstract: Mutational correlation patterns found in population-level sequence data for the Human Immunodeficiency Virus (HIV) and the Hepatitis C Virus (HCV) have been demonstrated to be informative of viral fitness. Such patterns can be seen as footprints of the intrinsic functional constraints placed on viral evolution under erse selective pressures. Here, considering multiple HIV and HCV proteins, we demonstrate that these mutational correlations encode a modular co-evolutionary structure that is tightly linked to the structural and functional properties of the respective proteins. Specifically, by introducing a robust statistical method based on sparse principal component analysis, we identify near-disjoint sets of collectively-correlated residues (sectors) having mostly a one-to-one association to largely distinct structural or functional domains. This suggests that the distinct phenotypic properties of HIV/HCV proteins often give rise to quasi-independent modes of evolution, with each mode involving a sparse and localized network of mutational interactions. Moreover, in idual inferred sectors of HIV are shown to carry immunological significance, providing insight for guiding targeted vaccine strategies. HIV and HCV cause devastating infectious diseases for which no functional vaccine exists. A key problem is that while immune cells may induce in idual mutations that compromise viral fitness, this is typically restored through other “compensatory” mutations, leading to immune escape. These compensatory pathways are complicated and remain poorly understood. They do, however, leave co-evolutionary markers which may be inferred from measured sequence data. Here, by introducing a new robust statistical method, we demonstrated that the compensatory networks employed by both viruses exhibit a remarkably simple decomposition involving small and near-distinct groups of protein residues, with most groups having a clear association to biological function or structure. This provides insights that can be harnessed for the purpose of vaccine design.
Publisher: IEEE
Date: 11-2016
Publisher: Springer Science and Business Media LLC
Date: 31-03-2023
DOI: 10.1038/S41467-023-37468-Y
Abstract: Viral and host factors can shape SARS-CoV-2 evolution. However, little is known about lineage-specific and vaccination-specific mutations that occur within in iduals. Here, we analysed deep sequencing data from 2,820 SARS-CoV-2 respiratory s les with different viral lineages to describe the patterns of within-host ersity under different conditions, including vaccine-breakthrough infections. In unvaccinated in iduals, variant of Concern (VOC) Alpha, Delta, and Omicron respiratory s les were found to have higher within-host ersity and were under neutral to purifying selection at the full genome level compared to non-VOC SARS-CoV-2. Breakthrough infections in 2-dose or 3-dose Comirnaty and CoronaVac vaccinated in iduals did not increase levels of non-synonymous mutations and did not change the direction of selection pressure. Vaccine-induced antibody or T cell responses did not appear to have significant impact on within-host SARS-CoV-2 sequence ersification. Our findings suggest that vaccination does not increase exploration of SARS-CoV-2 protein sequence space and may not facilitate emergence of viral variants.
Publisher: Public Library of Science (PLoS)
Date: 21-09-2020
Publisher: Research Square Platform LLC
Date: 11-08-2022
DOI: 10.21203/RS.3.RS-1927944/V1
Abstract: Viral and host factors can shape SARS-CoV-2 within-host viral ersity and virus evolution. However, little is known about lineage-specific and vaccination-specific mutations that occur within in iduals. Here we analysed deep sequencing data from 2,146 SARS-CoV-2 s les with different viral lineages to describe the patterns of within-host ersity in different conditions, including vaccine-breakthrough infections. Variant of Concern (VOC) Alpha, Delta, and Omicron s les were found to have higher within-host nucleotide ersity while being under weaker purifying selection at full genome level compared to non-VOC SARS-CoV-2 viruses. Breakthrough Delta and Omicron infections in Comirnaty and CoronaVac vaccinated in iduals appeared to have higher within-host purifying selection at the full-genome and/or Spike gene levels. Vaccine-induced antibody or T cell responses did not appear to have significant impact on within-host SARS-CoV-2 evolution. Our findings suggest that vaccination does not increase SARS-CoV-2 protein sequence space and may not facilitate emergence of more viral variants.
Publisher: Springer Science and Business Media LLC
Date: 17-01-2020
DOI: 10.1038/S41467-019-14174-2
Abstract: Vaccination has essentially eradicated poliovirus. Yet, its mutation rate is higher than that of viruses like HIV, for which no effective vaccine exists. To investigate this, we infer a fitness model for the poliovirus viral protein 1 (vp1), which successfully predicts in vitro fitness measurements. This is achieved by first developing a probabilistic model for the prevalence of vp1 sequences that enables us to isolate and remove data that are subject to strong vaccine-derived biases. The intrinsic fitness constraints derived for vp1, a capsid protein subject to antibody responses, are compared with those of analogous HIV proteins. We find that vp1 evolution is subject to tighter constraints, limiting its ability to evade vaccine-induced immune responses. Our analysis also indicates that circulating poliovirus strains in unimmunized populations serve as a reservoir that can seed outbreaks in spatio-temporally localized sub-optimally immunized populations.
Publisher: Oxford University Press (OUP)
Date: 18-12-2019
DOI: 10.1093/BIOINFORMATICS/BTZ925
Abstract: Learning underlying correlation patterns in data is a central problem across scientific fields. Maximum entropy models present an important class of statistical approaches for addressing this problem. However, accurately and efficiently inferring model parameters are a major challenge, particularly for modern high-dimensional applications such as in biology, for which the number of parameters is enormous. Previously, we developed a statistical method, minimum probability flow–Boltzmann Machine Learning (MPF–BML), for performing fast and accurate inference of maximum entropy model parameters, which was applied to genetic sequence data to estimate the fitness landscape for the surface proteins of human immunodeficiency virus and hepatitis C virus. To facilitate seamless use of MPF–BML and encourage more widespread application to data in erse fields, we present a standalone cross-platform package of MPF–BML which features an easy-to-use graphical user interface. The package only requires the input data (protein sequence data or data of multiple configurations of a complex system with large number of variables) and returns the maximum entropy model parameters. The MPF–BML software is publicly available under the MIT License at hmedaq/MPF-BML-GUI. Supplementary data are available at Bioinformatics online.
Publisher: MDPI AG
Date: 31-03-2022
Abstract: Memory SARS-CoV-2-specific CD8+ T cell responses induced upon infection or COVID-19 vaccination have been important for protecting against severe COVID-19 disease while being largely robust against variants of concern (VOCs) observed so far. However, T cell immunity may be weakened by genetic mutations in future SARS-CoV-2 variants that lead to widespread T cell escape. The capacity for SARS-CoV-2 mutations to escape memory T cell responses requires comprehensive experimental investigation, though this is prohibited by the large number of SARS-CoV-2 mutations that have been observed. To guide targeted experimental studies, here we provide a screened list of potential SARS-CoV-2 T cell escape mutants. These mutants are identified as candidates for T cell escape as they lie within CD8+ T cell epitopes that are commonly targeted in in iduals and are predicted to abrogate HLA–peptide binding.
Publisher: IEEE
Date: 09-2011
Publisher: Oxford University Press (OUP)
Date: 28-06-2019
DOI: 10.1093/BIOINFORMATICS/BTZ524
Abstract: Patterns of mutational correlations, learnt from patient-derived sequences of human immunodeficiency virus (HIV) proteins, are informative of biochemically linked networks of interacting sites that may enable viral escape from the host immune system. Accurate identification of these networks is important for rationally designing vaccines which can effectively block immune escape pathways. Previous computational methods have partly identified such networks by examining the principal components (PCs) of the mutational correlation matrix of HIV Gag proteins. However, driven by a conservative approach, these methods analyze the few dominant (strongest) PCs, potentially missing information embedded within the sub-dominant (relatively weaker) ones that may be important for vaccine design. By using sequence data for HIV Gag, complemented by model-based simulations, we revealed that certain networks of interacting sites that appear important for vaccine design purposes are not accurately reflected by the dominant PCs. Rather, these networks are encoded jointly by both dominant and sub-dominant PCs. By incorporating information from the sub-dominant PCs, we identified a network of interacting sites of HIV Gag that associated very strongly with viral control. Based on this network, we propose several new candidates for a potent T-cell-based HIV vaccine. Accession numbers of all sequences used and the source code scripts for all analysis and figures reported in this work are available online at araz107/HIV-Gag-Immunogens. Supplementary data are available at Bioinformatics online.
Publisher: Cold Spring Harbor Laboratory
Date: 26-08-2020
DOI: 10.1101/2020.08.26.267724
Abstract: Knowledge of the epitopes of SARS-CoV-2 that are targeted by T cells in convalescent patients is important for understanding T cell immunity against COVID-19. This information can aid the design, development and assessment of COVID-19 vaccines, and inform novel diagnostic technologies. Here we provide a unified description and meta-analysis of emerging data of SARS-CoV-2 T cell epitopes compiled from 15 independent studies of cohorts of convalescent COVID-19 patients. Our analysis demonstrates the broad ersity of T cell epitopes that have been collectively recorded for SARS-CoV-2, while also identifying a selected set of immunoprevalent epitopes that induced consistent T cell responses in multiple cohorts and in a large fraction of tested patients. The landscape of SARS-CoV-2 T cell epitopes that we describe can help guide future immunological studies, including those related to vaccines and diagnostics. A web-based platform has been developed to help complement these efforts.
Publisher: Springer Science and Business Media LLC
Date: 02-08-2022
DOI: 10.1038/S41467-019-09819-1
Abstract: Isolation of broadly neutralizing human monoclonal antibodies (HmAbs) targeting the E2 glycoprotein of Hepatitis C virus (HCV) has sparked hope for effective vaccine development. Nonetheless, escape mutations have been reported. Ideally, a potent vaccine should elicit HmAbs that target regions of E2 that are most difficult to escape. Here, aimed at addressing this challenge, we develop a predictive in-silico evolutionary model for E2 that identifies one such region, a specific antigenic domain, making it an attractive target for a robust antibody response. Specific broadly neutralizing HmAbs that appear difficult to escape from are also identified. By providing a framework for identifying vulnerable regions of E2 and for assessing the potency of specific antibodies, our results can aid the rational design of an effective prophylactic HCV vaccine.
Publisher: Elsevier BV
Date: 2022
Publisher: Cold Spring Harbor Laboratory
Date: 03-02-2021
DOI: 10.1101/2021.02.02.429470
Abstract: Hepatitis C virus (HCV) is a leading cause of liver-associated disease and liver cancer. Of the major HCV subtypes, patients infected with subtype 1b have been associated with having a higher risk of developing chronic infection, cirrhosis and hepatocellular carcinoma. However, underlying reasons for this increased disease severity remain unknown. Here, we provide an evolutionary rationale, based on a comparative study of fitness landscape and in-host evolutionary models of the envelope glycoprotein 2 (E2) of HCV subtypes 1a and 1b. Our analysis demonstrates that a higher chronicity rate of subtype 1b may be attributed to lower fitness constraints, enabling 1b viruses to more easily escape antibody responses. More generally, our results suggest that differences in evolutionary constraints between HCV subtypes may be an important factor in mediating distinct disease outcomes. Our analysis also identifies antibodies that appear to be escape-resistant against both subtypes 1a and 1b, providing directions for the design of HCV vaccines having cross-subtype protection.
Publisher: Elsevier BV
Date: 04-2021
Publisher: MDPI AG
Date: 25-02-2020
DOI: 10.3390/V12030254
Abstract: The beginning of 2020 has seen the emergence of COVID-19 outbreak caused by a novel coronavirus, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). There is an imminent need to better understand this new virus and to develop ways to control its spread. In this study, we sought to gain insights for vaccine design against SARS-CoV-2 by considering the high genetic similarity between SARS-CoV-2 and SARS-CoV, which caused the outbreak in 2003, and leveraging existing immunological studies of SARS-CoV. By screening the experimentally-determined SARS-CoV-derived B cell and T cell epitopes in the immunogenic structural proteins of SARS-CoV, we identified a set of B cell and T cell epitopes derived from the spike (S) and nucleocapsid (N) proteins that map identically to SARS-CoV-2 proteins. As no mutation has been observed in these identified epitopes among the 120 available SARS-CoV-2 sequences (as of 21 February 2020), immune targeting of these epitopes may potentially offer protection against this novel virus. For the T cell epitopes, we performed a population coverage analysis of the associated MHC alleles and proposed a set of epitopes that is estimated to provide broad coverage globally, as well as in China. Our findings provide a screened set of epitopes that can help guide experimental efforts towards the development of vaccines against SARS-CoV-2.
Publisher: Cold Spring Harbor Laboratory
Date: 23-06-2022
DOI: 10.1101/2022.06.23.497143
Abstract: Starting May 2022, a novel cluster of monkeypox virus infections was detected in humans. This has spread rapidly to non-endemic countries and sparked global concern. Vaccinia virus vaccines have demonstrated high efficacy against monkeypox viruses in the past and are considered an important outbreak control measure. Viruses observed in the current outbreak carry distinct genetic variation that have the potential to affect vaccine-induced immune recognition. Here, by investigating genetic variation with respect to orthologous immunogenic vaccinia-virus proteins, we report data that anticipates vaccine-induced immune responses to remain highly cross-reactive against the newly observed monkeypox viruses.
Publisher: Cold Spring Harbor Laboratory
Date: 2022
DOI: 10.1101/2021.12.31.21268591
Abstract: New and more transmissible variants of SARS-CoV-2 have arisen multiple times over the course of the pandemic. Rapidly identifying mutations that affect transmission could facilitate outbreak control efforts and highlight new variants that warrant further study. Here we develop an analytical epidemiological model that infers the transmission effects of mutations from genomic surveillance data. Applying our model to SARS-CoV-2 data across many regions, we find multiple mutations that strongly affect the transmission rate, both within and outside the Spike protein. We also quantify the effects of travel and competition between different lineages on the inferred transmission effects of mutations. Importantly, our model detects lineages with increased transmission as they arise. We infer significant transmission advantages for the Alpha and Delta variants within a week of their appearances in regional data, when their regional frequencies were only around 1%. Our model thus enables the rapid identification of variants and mutations that affect transmission from genomic surveillance data.
Publisher: IEEE
Date: 06-2014
Publisher: Cold Spring Harbor Laboratory
Date: 04-02-2020
DOI: 10.1101/2020.02.03.933226
Abstract: The beginning of 2020 has seen the emergence of COVID-19 outbreak caused by a novel coronavirus, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). There is an imminent need to better understand this new virus and to develop ways to control its spread. In this study, we sought to gain insights for vaccine design against SARS-CoV-2 by considering the high genetic similarity between SARS-CoV-2 and SARS-CoV, which caused the outbreak in 2003, and leveraging existing immunological studies of SARS-CoV. By screening the experimentally-determined SARS-CoV-derived B cell and T cell epitopes in the immunogenic structural proteins of SARS-CoV, we identified a set of B cell and T cell epitopes derived from the spike (S) and nucleocapsid (N) proteins that map identically to SARS-CoV-2 proteins. As no mutation has been observed in these identified epitopes among the available SARS-CoV-2 sequences (as of 9 February 2020), immune targeting of these epitopes may potentially offer protection against this novel virus. For the T cell epitopes, we performed a population coverage analysis of the associated MHC alleles and proposed a set of epitopes that is estimated to provide broad coverage globally, as well as in China. Our findings provide a screened set of epitopes that can help guide experimental efforts towards the development of vaccines against SARS-CoV-2.
Publisher: MDPI AG
Date: 02-01-2022
DOI: 10.3390/V14010079
Abstract: Omicron, the most recent SARS-CoV-2 variant of concern (VOC), harbours multiple mutations in the spike protein that were not observed in previous VOCs. Initial studies suggest Omicron to substantially reduce the neutralizing capability of antibodies induced from vaccines and previous infection. However, its effect on T cell responses remains to be determined. Here, we assess the effect of Omicron mutations on known T cell epitopes and report data suggesting T cell responses to remain broadly robust against this new variant.
Publisher: Cold Spring Harbor Laboratory
Date: 24-05-2020
DOI: 10.1101/2020.05.23.111385
Abstract: We introduce COVIDep ( COVIDep.ust.hk ), a web-based platform that provides immune target recommendations for guiding SARS-CoV-2 vaccine development. COVIDep implements a protocol that pools together publicly-available genetic data for SARS-CoV-2 and epitope data for SARS-CoV to identify B cell and T cell epitopes that present potential immune targets for SARS-CoV-2. Correspondences between outputs of COVIDep and immune responses recorded in COVID-19 patients and preclinical vaccine trials are also indicated. The platform is user-friendly, flexible, and based on up-to-date data. It may help guide vaccine designs and associated experimental studies for SARS-CoV-2.
Publisher: Public Library of Science (PLoS)
Date: 07-09-2018
Publisher: IEEE
Date: 02-2013
Publisher: Cold Spring Harbor Laboratory
Date: 07-04-2023
DOI: 10.1101/2023.04.03.535505
Abstract: The Hepatitis C virus (HCV) envelope glycoprotein E1 forms a noncovalent heterodimer with E2, the main target of neutralizing antibodies. How E1-E2 interactions influence viral fitness and contribute to resistance to E2-specific antibodies remains largely unknown. We investigate this problem using a combination of fitness landscape and evolutionary modelling. Our analysis indicates that E1 and E2 proteins collectively mediate viral fitness, and suggests that fitness-compensating E1 mutations may accelerate escape from E2-targeting antibodies. Our analysis also identifies a set of E2-specific human monoclonal antibodies that are predicted to be especially resilient to escape via genetic variation in both E1 and E2, providing directions for robust HCV vaccine development.
Publisher: American Society for Microbiology
Date: 07-2014
DOI: 10.1128/JVI.03812-13
Abstract: Chronic hepatitis C virus (HCV) infection is one of the leading causes of liver failure and liver cancer, affecting around 3% of the world's population. The extreme sequence variability of the virus resulting from error-prone replication has thwarted the discovery of a universal prophylactic vaccine. It is known that vigorous and multispecific cellular immune responses, involving both helper CD4 + and cytotoxic CD8 + T cells, are associated with the spontaneous clearance of acute HCV infection. Escape mutations in viral epitopes can, however, abrogate protective T-cell responses, leading to viral persistence and associated pathologies. Despite the propensity of the virus to mutate, there might still exist substitutions that incur a fitness cost. In this paper, we identify groups of coevolving residues within HCV nonstructural protein 3 (NS3) by analyzing erse sequences of this protein using ideas from random matrix theory and associated methods. Our analyses indicate that one of these groups comprises a large percentage of residues for which HCV appears to resist multiple simultaneous substitutions. Targeting multiple residues in this group through vaccine-induced immune responses should either lead to viral recognition or elicit escape substitutions that compromise viral fitness. Our predictions are supported by published clinical data, which suggested that immune genotypes associated with spontaneous clearance of HCV preferentially recognized and targeted this vulnerable group of residues. Moreover, mapping the sites of this group onto the available protein structure provided insight into its functional significance. An epitope-based immunogen is proposed as an alternative to the NS3 epitopes in the peptide-based vaccine IC41. IMPORTANCE Despite much experimental work on HCV, a thorough statistical study of the HCV sequences for the purpose of immunogen design was missing in the literature. Such a study is vital to identify epistatic couplings among residues that can provide useful insights for designing a potent vaccine. In this work, ideas from random matrix theory were applied to characterize the statistics of substitutions within the erse publicly available sequences of the genotype 1a HCV NS3 protein, leading to a group of sites for which HCV appears to resist simultaneous substitutions possibly due to deleterious effect on viral fitness. Our analysis leads to completely novel immunogen designs for HCV. In addition, the NS3 epitopes used in the recently proposed peptide-based vaccine IC41 were analyzed in the context of our framework. Our analysis predicts that alternative NS3 epitopes may be worth exploring as they might be more efficacious.
Publisher: Elsevier BV
Date: 06-2021
Location: Saudi Arabia
Start Date: 2023
End Date: 12-2025
Amount: $425,000.00
Funder: Australian Research Council
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