Biology subjects

Lewitus, E.

Publications and source records attributed to Lewitus, E..

5 recordsLinked to original sources

bioRxiv2023

Contemporary HIV-1 consensus Env with redesigned hypervariable loops promote antibody binding

An effective HIV-1 vaccine must elicit broadly neutralizing antibodies (bnAbs) against the highly diverse Envelope glycoproteins (Env) present globally. Since Env with the longest hypervariable (HV) loops were more resistant to the cognate bnAbs than Env with shorter HV loops, we redesigned hypervariable loops for updated HIV-1 Env consensus sequences of subtypes B and C and circulating recombinant form AE (CRF01_AE). We reduced the length of V1HV, V2H, and V5HV while maintaining the integrity of the Env structure and glycan shield, and we modified V4HV to account for its diverse structural context. Redesiged HV loops consisted mainly of glycine and serine to limit strain-specific targeting. Redesigned consensus Env of subtype B or CRF01_AE demonstrated increased magnitude of binding responses to pooled plasma samples and representative bnAbs. Together with other antigen optimization techniques, consensus Env with redesigned hypervariable loops can improve future HIV-1 vaccine antigens to elicit bnAbs.

microbiology↗

bioRxiv2021

Monocyte-derived transcriptome signature indicates antibody-dependent cellular 1 phagocytosis as the primary mechanism of vaccine-induced protection against HIV-1

A gene signature previously correlated with mosaic adenovirus 26 vaccine protection in simian immunodeficiency virus (SIV) and SHIV challenge models in non-human primates (NHP). In this report we investigated presence of this signature as a correlate of reduced risk in human clinical trials and potential mechanism for protection. The absence of this gene signature in the DNA/rAd5 human vaccine trial which did not show efficacy, strengthens our hypothesis that this signature is only enriched in studies that demonstrated protection. This gene signature was enriched in the partially effective RV144 human trial that administered the ALVAC/protein vaccine, and we find that the signature associates with both decreased risk of HIV-1 acquisition and increased vaccine efficacy. Total RNA-seq in a clinical trial that used the same vaccine regimen as the RV144 HIV vaccine implicated antibody-dependent cellular phagocytosis (ADCP) as a potential mechanism of vaccine protection. CITE-seq profiling of 53 surface markers and transcriptomes of 53,777 single cells from the same trial, showed that genes in this signature were primarily expressed in cells belonging to the myeloid lineage including monocytes, which are major effector cells for ADCP. The consistent association of this transcriptome signature with vaccine efficacy represents a tool both to identify potential mechanisms, as with ADCP here, and to screen novel approaches to accelerate development of new vaccine candidates.

systems biology↗

bioRxiv2020

A SARS-CoV-2 vaccine candidate would likely match all currently circulating strains

The magnitude of the COVID-19 pandemic underscores the urgency for a safe and effective vaccine. Here we analyzed SARS-CoV-2 sequence diversity across 5,700 sequences sampled since December 2019. The Spike protein, which is the target immunogen of most vaccine candidates, showed 93 sites with shared polymorphisms; only one of these mutations was found in more than 1% of currently circulating sequences. The minimal diversity found among SARS-CoV-2 sequences can be explained by drift and bottleneck events as the virus spread away from its original epicenter in Wuhan, China. Importantly, there is little evidence that the virus has adapted to its human host since December 2019. Our findings suggest that a single vaccine should be efficacious against current global strains. One Sentence SummaryThe limited diversification of SARS-CoV-2 reflects drift and bottleneck events rather than adaptation to humans as the virus spread.

evolutionary biology↗

bioRxiv2019

Characterizing and comparing phylogenetic trait data from their normalized Laplacian spectrum

The dissection of the mode and tempo of phenotypic evolution is integral to our understanding of global biodiversity. Our ability to infer patterns of phenotypes across phylogenetic clades is essential to how we infer the macroevolutionary processes governing those patterns. Many methods are already available for fitting models of phenotypic evolution to data. However, there is currently no non-parametric comprehensive framework for characterising and comparing patterns of phenotypic evolution. Here we build on a recently introduced approach for using the phylogenetic spectral density profile to compare and characterize patterns of phylogenetic diversification, in order to provide a framework for non-parametric analysis of phylogenetic trait data. We show how to construct the spectral density profile of trait data on a phylogenetic tree from the normalized graph Laplacian. We demonstrate on simulated data the utility of the spectral density profile to successfully cluster phylogenetic trait data into meaningful groups and to characterise the phenotypic patterning within those groups. We furthermore demonstrate how the spectral density profile is a powerful tool for visualising phenotypic space across traits and for assessing whether distinct trait evolution models are distinguishable on a given empirical phylogeny. We illustrate the approach in two empirical datasets: a comprehensive dataset of traits involved in song, plumage and resource-use in tanagers, and a high-dimensional dataset of endocranial landmarks in New World monkeys. Considering the proliferation of morphometric and molecular data collected across the tree of life, we expect this approach will benefit big data analyses requiring a comprehensive and intuitive framework.

evolutionary biology↗

bioRxiv2017

Detecting environment-dependent diversification from phylogenies: a simulation study and some empirical illustrations

Understanding the relative influence of various abiotic and biotic variables on diversification dynamics is a major goal of macroevolutionary studies. Recently, phylogenetic approaches have been developed that make it possible to estimate the role of various environmental variables on diversification using time-calibrated species trees, paleoenvironmental data, and maximum-likelihood techniques. These approaches have been effectively employed to estimate how speciation and extinction rates vary with key abiotic variables, such as temperature and sea level, and we can anticipate that they will be increasingly used in the future. Here we compile a series of biotic and abiotic paleodatasets that can be used as explanatory variables in these models and use simulations to assess the statistical properties of the approach when applied to these paleodatasets. We demonstrate that environment-dependent models perform well in recovering environment-dependent speciation and extinction parameters, as well as in correctly identifying the simulated environmental model when speciation isenvironment-dependent. We explore how the strength of the environment-dependency, tree size, missing taxa, and characteristics of the paleoenvironmental curves influence the performance of the models. Finally, using these models, we infer environment-dependent diversification in three empirical phylogenies: temperature-dependence in Cetacea,{delta} 13C-dependence in Ruminantia, and CO2-dependence in Portulacaceae. We illustrate how to evaluate the relative importance of abiotic and biotic variables in these three clades and interpret these results in light of macroevolutionary hypotheses for mammals and plants. Given the important role paleoenvironments are presumed to have played in species evolution, our statistical assessment of how environment-dependent models behave is crucial for their utility in macroevolutionary analysis.

evolutionary biology↗