Viral reassortment as an information exchange between viral segments

Abstract

Viruses have an extraordinary ability to diversify and evolve. For segmented viruses, reassortment can introduce drastic genomic and phenotypic changes by allowing a direct exchange of genetic material between coinfecting strains. For instance, multiple influenza pandemics were caused by reassortments of viruses typically found in separate hosts. What is unclear, however, are the underlying mechanisms driving these events and the level of intrinsic bias in the diversity of strains that emerge from coinfection. To address this problem, previous experiments looked for correlations between segments of strains that coinfect cells in vitro. Here, we present an information theory approach as the natural mathematical framework for this question. We study, for influenza and other segmented viruses, the extent to which a virus's segments can communicate strain information across an infection and among one another. Our approach goes beyond previous association studies and quantifies how much the diversity of emerging strains is altered by patterns in reassortment, whether biases are consistent across multiple strains and cell types, and if significant information is shared among more than two segments. We apply our approach to a new experiment that examines reassortment patterns between the 2009 H1N1 pandemic and seasonal H1N1 strains, contextualizing its segmental information sharing by comparison with previously reported strain reassortments. We find evolutionary patterns across classes of experiments and previously unobserved higher-level structures. Finally, we show how this approach can be combined with virulence potentials to assess pandemic threats. viral evolution | systems biology | emerging infectious disease R eassortment of segmented viruses is a key mechanism for rapid novel virus creation. At least two human influenza pandemics in the last century were linked to lineages where some number of genomic segments reassorted with a genome of nonhuman origin (1, 2). This fact was reinforced by the emergence of the 2009 H1N1 pandemic (2009 pdm) virus (3-5). Novel reassortant strains can evade adaptive immunity by introducing antigens to a naïve host population or overly stimulate innate immunity by presenting a new host with abundant nonself molecular signals (6-10). Moreover, both sequence database studies and in vitro experiments have shown that genome reassortment between strains happens nonrandomly: If two strains coinfect the same cell, their progeny may not sample all possible strain/segment combinations uniformly (11)(12)(13)(14). These analyses focused on whether it is more likely that pairs of segments from the same strain appear together in reassortments, typically using chi-square tests to establish significance.Because influenza has eight segments, there are 256 possible reassortant viruses when a cell is coinfected by two strains. Each strain type and host cellular environment can influence reassortment differently, so it would seem impossible to predict whether a new pandemic strain can form. However, ...

Development of live-attenuated arenavirus vaccines based on codon deoptimization of the viral glycoprotein

“…The ML29 reassortant is a promising LASV LAV that has been shown to provide effective protection in different animal models of LASV induced disease (Carrion et al, 2007; Lukashevich et al, 2005, 2008). However, the mechanisms responsible for ML29 attenuation remain unknown (Olschlager and Flatz, 2013), and therefore the incorporation of a limited number of additional mutations into the ML29 genome might result in viruses with enhanced virulence (Greenbaum et al, 2012). Similarly, the phenotypic stability of Candid#1, the JUNV LAV, has not been fully examined and safety concerns have recently arose since a single amino acid substitution (F427I) in the GP of the pathogenic JUNV XJ13 leads to an Candid#1-like attenuated phenotype (Albarino et al, 2011; Droniou-Bonzom et al, 2011), suggesting that a limited number of mutations could result in reversion of Candid#1 into a more virulent strain.…”

“…Differences in polymerase activity between LASV and MOPV likely contributed to ML29 attenuation but the mechanisms of attenuation of ML29 remain unknown, which raises concerns about whether the acquisition of additional mutations by the L polymerase of ML29 could result in increased virulence. Likewise, there are concerns that potential reassortants between ML29 and circulating virulent strains of LASV could result in viruses with enhanced virulence (Greenbaum et al, 2012). Therefore, there is an unmet need for novel strategies to develop safe and effective LAV against disease caused by arenavirus infections.…”

Coinfection dynamics of two diseases in a single host population

“…Many examples can be found, these involving HIV [30, 37] (for example, HIV and TB [19], HIV and Hepatitis B [12, 26], HIV and Hepatitis C [23], and HIV and malaria [2]), as well as some not involving HIV (for example, Hepatitis B and C coinfection [11], gonorrhea and Chlamydia [13], and herpes simplex viruses 1 and 2 [41, 59]) Moreover, simultaneous infection may occur with multiple strains or serotypes of the same organism, as is the case for influenza [20, 49], human papilloma virus [9], and HIV [55, 63, 22], for just three of many examples. However, simultaneous colonization or infection may occur even when there appears to be little or no interaction between the two agents, as in the case of infection by ocular strains of chlamydia and nasopharyngeal colonization by pneumococcus [24].…”

Viral evolution: beyond drift and shift

“…This increase in data has sparked a need for more general quantitative methods that allow comparison between effect size and significance. In one such study [28], information theory was used to compare reassortment patterns among several experiments for both different influenza strains and other segmented viruses. This approach is well-suited for quantifying, in an unbiased manner, the strength of association between variables [29 ].…”