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Register a new userLongitudinal Antigenic Sequences and Sites from Intra-Host Evolution (LASSIE) Identifies Immune-Selected HIV Variants
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Within-host genetic sequencing from samples collected over time provides a dynamic view of how viruses evade host immunity. Immune-driven mutations might stimulate neutralization breadth by selecting antibodies adapted to cycles of immune escape that generate within-subject epitope diversity. Comprehensive identification of immune-escape mutations is experimentally and computationally challenging. With current technology, many more viral sequences can readily be obtained than can be tested for binding and neutralization, making down-selection necessary. Typically, this is done manually, by picking variants that represent different time-points and branches on a phylogenetic tree. Such strategies are likely to miss many relevant mutations and combinations of mutations, and to be redundant for other mutations. Longitudinal Antigenic Sequences and Sites from Intrahost Evolution (LASSIE) uses transmitted-founder loss to identify virus hot-spots under putative immune selection and chooses sequences that represent recurrent mutations in selected sites. LASSIE favors earliest sequences in which mutations arise. With well-characterized longitudinal Env sequences, we confirmed selected sites were concentrated in antibody contacts and selected sequences represented diverse antigenic phenotypes. Practical applications include rapidly identifying immune targets under selective pressure within a subject, selecting minimal sets of reagents for immunological assays that characterize evolving antibody responses, and for immunogens in polyvalent cocktail vaccines.
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The transmission and evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are of paramount importance to the controlling and combating of coronavirus disease 2019 (COVID-19) pandemic. Currently, near 15,000 SARS-CoV-2 single mutations have been recorded, having a great ramification to the development of diagnostics, vaccines, antibody therapies, and drugs. However, little is known about SARS-CoV-2 evolutionary characteristics and general trend. In this work, we present a comprehensive genotyping analysis of existing SARS-CoV-2 mutations. We reveal that host immune response via APOBEC and ADAR gene editing gives rise to near 65% of recorded mutations. Additionally, we show that children under age five and the elderly may be at high risk from COVID-19 because of their overreacting to the viral infection. Moreover, we uncover that populations of Oceania and Africa react significantly more intensively to SARS-CoV-2 infection than those of Europe and Asia, which may explain why African Americans were shown to be at increased risk of dying from COVID-19, in addition to their high risk of getting sick from COVID-19 caused by systemic health and social inequities. Finally, our study indicates that for two viral genome sequences of the same origin, their evolution order may be determined from the ratio of mutation type C$>$T over T$>$C.
Immune checkpoint therapy is one of the most promising immunotherapeutic methods that are likely able to give rise to durable treatment response for various cancer types. Despite much progress in the past decade, there are still critical open questions with particular regards to quantifying and predicting the efficacy of treatment and potential optimal regimens for combining different immune-checkpoint blockades. To shed light on this issue, here we develop clinically-relevant, dynamical systems models of cancer immunotherapy with a focus on the immune checkpoint PD-1/PD-L1 blockades. Our model allows the acquisition of adaptive immune resistance in the absence of treatment, whereas immune checkpoint blockades can reverse such resistance and boost anti-tumor activities of effector cells. Our numerical analysis predicts that anti-PD-1 agents are commonly less effective than anti-PD-L1 agents for a wide range of model parameters. We also observe that combination treatment of anti-PD-1 and anti-PD-L1 blockades leads to a desirable synergistic effect. Our modeling framework lays the ground for future data-driven analysis on combination therapeutics of immune-checkpoint treatment regimes and thorough investigation of optimized treatment on a patient-by-patient basis.
We consider a continuous-time Markov chain model of SIR disease dynamics with two levels of mixing. For this so-called stochastic households model, we provide two methods for inferring the model parameters---governing within-household transmission, recovery, and between-household transmission---from data of the day upon which each individual became infectious and the household in which each infection occurred, as would be available from first few hundred studies. Each method is a form of Bayesian Markov Chain Monte Carlo that allows us to calculate a joint posterior distribution for all parameters and hence the household reproduction number and the early growth rate of the epidemic. The first method performs exact Bayesian inference using a standard data-augmentation approach; the second performs approximate Bayesian inference based on a likelihood approximation derived from branching processes. These methods are compared for computational efficiency and posteriors from each are compared. The branching process is shown to be an excellent approximation and remains computationally efficient as the amount of data is increased.
A molecular dynamics calculation of the amino acid polar requirement is presented and used to score the canonical genetic code. Monte Carlo simulation shows that this computational polar requirement has been optimized by the canonical genetic code more than any previously-known measure. These results strongly support the idea that the genetic code evolved from a communal state of life prior to the root of the modern ribosomal tree of life.
Increasing number in global COVID-19 cases demands for mathematical model to analyze the interaction between the virus dynamics and the response of innate and adaptive immunity. Here, based on the assumption of a weak and delayed response of the innate and adaptive immunity in SARS-CoV-2 infection, we constructed a mathematical model to describe the dynamic processes of immune system. Integrating theoretical results with clinical COVID-19 patients data, we classified the COVID-19 development processes into three typical modes of immune responses, correlated with the clinical classification of mild & moderate, severe and critical patients. We found that the immune efficacy (the ability of host to clear virus and kill infected cells) and the lymphocyte supply (the abundance and pool of naive T and B cell) play important roles in the dynamic process and determine the clinical outcome, especially for the severe and critical patients. Furthermore, we put forward possible treatment strategies for the three typical modes of immune response. We hope our results can help to understand the dynamical mechanism of the immune response against SARS-CoV-2 infection, and to be useful for the treatment strategies and vaccine design.
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