The Evolutionary Dynamics of a Rapidly Mutating Virus within and between Hosts: The Case of Hepatitis C Virus

Many pathogens associated with chronic infections evolve so rapidly that strains found late in an infection have little in common with the initial strain. This raises questions at different levels of analysis because rapid within-host evolution affects the course of an infection, but it can also affect the possibility for natural selection to act at the between-host level. We present a nested approach that incorporates within-host evolutionary dynamics of a rapidly mutating virus (hepatitis C virus) targeted by a cellular cross-reactive immune response, into an epidemiological perspective. The viral trait we follow is the replication rate of the strain initiating the infection. We find that, even for rapidly evolving viruses, the replication rate of the initial strain has a strong effect on the fitness of an infection. Moreover, infections caused by slowly replicating viruses have the highest infection fitness (i.e., lead to more secondary infections), but strains with higher replication rates tend to dominate within a host in the long-term. We also study the effect of cross-reactive immunity and viral mutation rate on infection life history traits. For instance, because of the stochastic nature of our approach, we can identify factors affecting the outcome of the infection (acute or chronic infections). Finally, we show that anti-viral treatments modify the value of the optimal initial replication rate and that the timing of the treatment administration can have public health consequences due to within-host evolution. Our results support the idea that natural selection can act on the replication rate of rapidly evolving viruses at the between-host level. It also provides a mechanistic description of within-host constraints, such as cross-reactive immunity, and shows how these constraints affect the infection fitness. This model raises questions that can be tested experimentally and underlines the necessity to consider the evolution of quantitative traits to understand the outcome and the fitness of an infection

Epidemics with mutating infectivity on small-world networks

Epidemics and evolution of many pathogens occur on similar timescales so that their dynamics are often entangled. Here, in a first step to study this problem theoretically, we analyze mutating pathogens spreading on simple SIR networks with grid-like connectivity. We have in mind the spatial aspect of epidemics, which often advance on transport links between hosts or groups of hosts such as cities or countries. We focus on the case of mutations that enhance an agent’s infection rate. We uncover that the small-world property, i.e., the presence of long-range connections, makes the network very vulnerable, supporting frequent supercritical mutations and bringing the network from disease extinction to full blown epidemic. For very large numbers of long-range links, however, the effect reverses and we find a reduced chance for large outbreaks. We study two cases, one with discrete number of mutational steps and one with a continuous genetic variable, and we analyze various scaling regimes. For the continuous case we derive a Fokker-Planck-like equation for the probability density and solve it for small numbers of shortcuts using the WKB approximation. Our analysis supports the claims that a potentiating mutation in the transmissibility might occur during an epidemic wave and not necessarily before its initiation. © 2020, The Author(s)

Epidemics with mutating infectivity on small-world networks

Epidemics and evolution of many pathogens occur on similar timescales so that their dynamics are often entangled. Here, in a first step to study this problem theoretically, we analyze mutating pathogens spreading on simple SIR networks with grid-like connectivity. We have in mind the spatial aspect of epidemics, which often advance on transport links between hosts or groups of hosts such as cities or countries. We focus on the case of mutations that enhance an agent's infection rate. We uncover that the small-world property, i.e., the presence of long-range connections, makes the network very vulnerable, supporting frequent supercritical mutations and bringing the network from disease extinction to full blown epidemic. For very large numbers of long-range links, however, the effect reverses and we find a reduced chance for large outbreaks. We study two cases, one with discrete number of mutational steps and one with a continuous genetic variable, and we analyze various scaling regimes. For the continuous case we derive a Fokker-Planck-like equation for the probability density and solve it for small numbers of shortcuts using the WKB approximation. Our analysis supports the claims that a potentiating mutation in the transmissibility might occur during an epidemic wave and not necessarily before its initiation

Impact of viral drift on vaccination dynamics and patterns of seasonal influenza

BACKGROUND: Much research has been devoted to the determination of optimal vaccination strategies for seasonal influenza epidemics. However, less attention has been paid to whether this optimization can be achieved within the context of viral drift. METHODS: We developed a mathematical model that links different intra-seasonal dynamics of vaccination and infection to investigate the effect of viral drift on optimal vaccination for minimizing the total number of infections. The model was computationally implemented using a seasonal force of infection, with estimated parameters from the published literature. RESULTS: Simulation results show that the pattern of large seasonal epidemics is strongly correlated with the duration of specific cross-protection immunity induced by natural infection. Considering a random vaccination, our simulations suggest that the effect of vaccination on epidemic patterns is largely influenced by the duration of protection induced by strain-specific vaccination. We found that the protection efficacy (i.e., reduction of susceptibility to infection) of vaccine is a parameter that could influence these patterns, particularly when the duration of vaccine-induced cross-protection is lengthened. CONCLUSIONS: Given the uncertainty in the timing and nature of antigenically drifted variants, the findings highlight the difficulty in determining optimal vaccination dynamics for seasonal epidemics. Our study suggests that the short- and long-term impacts of vaccination on seasonal epidemics should be evaluated within the context of population-pathogen landscape for influenza evolution

Persisting Viral Sequences Shape Microbial CRISPR-based Immunity

Well-studied innate immune systems exist throughout bacteria and archaea, but a more recently discovered genomic locus may offer prokaryotes surprising immunological adaptability. Mediated by a cassette-like genomic locus termed Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR), the microbial adaptive immune system differs from its eukaryotic immune analogues by incorporating new immunities unidirectionally. CRISPR thus stores genomically recoverable timelines of virus-host coevolution in natural organisms refractory to laboratory cultivation. Here we combined a population genetic mathematical model of CRISPR-virus coevolution with six years of metagenomic sequencing to link the recoverable genomic dynamics of CRISPR loci to the unknown population dynamics of virus and host in natural communities. Metagenomic reconstructions in an acid-mine drainage system document CRISPR loci conserving ancestral immune elements to the base-pair across thousands of microbial generations. This ‘trailer-end conservation’ occurs despite rapid viral mutation and despite rapid prokaryotic genomic deletion. The trailer-ends of many reconstructed CRISPR loci are also largely identical across a population. ‘Trailer-end clonality’ occurs despite predictions of host immunological diversity due to negative frequency dependent selection (kill the winner dynamics). Statistical clustering and model simulations explain this lack of diversity by capturing rapid selective sweeps by highly immune CRISPR lineages. Potentially explaining ‘trailer-end conservation,’ we record the first example of a viral bloom overwhelming a CRISPR system. The polyclonal viruses bloom even though they share sequences previously targeted by host CRISPR loci. Simulations show how increasing random genomic deletions in CRISPR loci purges immunological controls on long-lived viral sequences, allowing polyclonal viruses to bloom and depressing host fitness. Our results thus link documented patterns of genomic conservation in CRISPR loci to an evolutionary advantage against persistent viruses. By maintaining old immunities, selection may be tuning CRISPR-mediated immunity against viruses reemerging from lysogeny or migration

Highly Mutable Linker Regions Regulate HIV-1 Rev Function and Stability.

HIV-1 Rev is an essential viral regulatory protein that facilitates the nuclear export of intron-containing viral mRNAs. It is organized into structured, functionally well-characterized motifs joined by less understood linker regions. Our recent competitive deep mutational scanning study confirmed many known constraints in Rev's established motifs, but also identified positions of mutational plasticity, most notably in surrounding linker regions. Here, we probe the mutational limits of these linkers by testing the activities of multiple truncation and mass substitution mutations. We find that these regions possess previously unknown structural, functional or regulatory roles, not apparent from systematic point mutational approaches. Specifically, the N- and C-termini of Rev contribute to protein stability; mutations in a turn that connects the two main helices of Rev have different effects in different contexts; and a linker region which connects the second helix of Rev to its nuclear export sequence has structural requirements for function. Thus, Rev function extends beyond its characterized motifs, and is tuned by determinants within seemingly plastic portions of its sequence. Additionally, Rev's ability to tolerate many of these massive truncations and substitutions illustrates the overall mutational and functional robustness inherent in this viral protein