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Sergeev, Rinat

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Sergeev

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Rinat

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Sergeev, Rinat

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2014 - 20192

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Author's Publications: search.filters.isAuthorOfPublication.857bc74c-d3ec-42a6-8c68-93d7576eb3dd

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    The Route of HIV Escape from Immune Response Targeting Multiple Sites Is Determined by the Cost-Benefit Tradeoff of Escape Mutations
    (Public Library of Science, 2014-08-05) Batorsky, Rebecca E.; Sergeev, Rinat; Rouzine, Igor M.
    Cytotoxic T lymphocytes (CTL) are a major factor in the control of HIV replication. CTL arise in acute infection causing escape mutations to spread rapidly through the population of infected cells. As a result, the virus develops partial resistance to the immune response. The factors controlling the order of mutating epitope sites are currently unknown and would provide a valuable tool for predicting conserved epitopes. In this work, we adapt a well-established mathematical model of HIV evolution under dynamical selection pressure from multiple CTL clones to include partial impairment of CTL recognition, ∆r, as well as cost to viral replication, ∆f. The process of escape is described in terms of the cost-benefit tradeoff of escape mutations and predicts a trajectory in the cost-benefit plane connecting sequentially escaped sites, which moves from high recognition loss/low fitness cost to low recognition loss/high fitness cost and has a larger slope for early escapes than for late escapes. The slope of the trajectory offers an interpretation of positive correlation between fitness costs and HLA binding impairment to HLA-A molecules and a protective subset of HLA-B molecules that was observed for clinically relevant escape mutations in the Pol gene. We estimate the value of ∆r from published experimental studies to be in the range (0.01-0.86) and show that the assumption of complete recognition loss (∆r = 1) leads to an overestimate of mutation cost. Our analysis offers a consistent interpretation of the commonly observed pattern of escape, in which several escape mutations are observed transiently in an epitope. This non-nested pattern is a combined effect of temporal changes in selection pressure and partial recognition loss. We conclude that partial recognition loss is as important as fitness loss for predicting the order of escapes and, ultimately, for predicting conserved epitopes that can be targeted by vaccines.
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    Advancing Computational Biology and Bioinformatics Research through Open Innovation Competitions
    (Public Library of Science (PLoS), 2019-09-27) Blasco, Andrea; Endres, Michael; Sergeev, Rinat; Jonchhe, Anup; Macaluso, N. J. Maximilian; Narayan, Rajiv; Natoli, Ted; Paik, Jin; Briney, Bryan; Wu, Chunlei; Su, Andrew I.; Subramanian, Aravind; Lakhani, Karim
    Open data science and algorithm development competitions offer a unique avenue for rapid discovery of better computational strategies. We highlight three examples in computational biology and bioinformatics research where the use of competitions has yielded significant performance gains over established algorithms. These include studying algorithms for antibody clustering, imputing gene expression data, and querying the Connectivity Map (CMap). Performance gains are evaluated quantitatively using realistic, albeit sanitized, data sets. The solutions produced through these competitions are then examined with respect to their utility and the prospects for implementation in the field. We present the decision process and competition design considerations that lead to these successful outcomes as a model for researchers who want to use competitions and non-domain crowds as collaborators to further their research.