Short-Sighted Virus Evolution and a Germline Hypothesis for Chronic Viral Infections
2017; Elsevier BV; Volume: 25; Issue: 5 Linguagem: Inglês
10.1016/j.tim.2017.03.003
ISSN1878-4380
AutoresKatrina Lythgoe, Andy Gardner, Oliver G. Pybus, Joe Grove,
Tópico(s)Animal Disease Management and Epidemiology
ResumoAdaptive evolutionary change of viruses within hosts can be detrimental to onward transmission (short-sighted evolution). Loss of transmissibility is likely to be most problematical for rapidly evolving persistent (chronic) viral infections. Within-host viral populations or subpopulations can exhibit lower rates of evolution that expected. Selection probably occurs at the point of transmission, often leading to only one or a few viruses establishing new infections. The preferential transmission of founder-like viruses that have undergone little within-host evolution has been proposed. With extremely short generation times and high mutability, many viruses can rapidly evolve and adapt to changing environments. This ability is generally beneficial to viruses as it allows them to evade host immune responses, evolve new behaviours, and exploit ecological niches. However, natural selection typically generates adaptation in response to the immediate selection pressures that a virus experiences in its current host. Consequently, we argue that some viruses, particularly those characterised by long durations of infection and ongoing replication, may be susceptible to short-sighted evolution, whereby a virus' adaptation to its current host will be detrimental to its onward transmission within the host population. Here we outline the concept of short-sighted viral evolution and provide examples of how it may negatively impact viral transmission among hosts. We also propose that viruses that are vulnerable to short-sighted evolution may exhibit strategies that minimise its effects. We speculate on the various mechanisms by which this may be achieved, including viral life history strategies that result in low rates of within-host evolution, or the establishment of a 'germline' lineage of viruses that avoids short-sighted evolution. These concepts provide a new perspective on the way in which some viruses have been able to establish and maintain global pandemics. With extremely short generation times and high mutability, many viruses can rapidly evolve and adapt to changing environments. This ability is generally beneficial to viruses as it allows them to evade host immune responses, evolve new behaviours, and exploit ecological niches. However, natural selection typically generates adaptation in response to the immediate selection pressures that a virus experiences in its current host. Consequently, we argue that some viruses, particularly those characterised by long durations of infection and ongoing replication, may be susceptible to short-sighted evolution, whereby a virus' adaptation to its current host will be detrimental to its onward transmission within the host population. Here we outline the concept of short-sighted viral evolution and provide examples of how it may negatively impact viral transmission among hosts. We also propose that viruses that are vulnerable to short-sighted evolution may exhibit strategies that minimise its effects. We speculate on the various mechanisms by which this may be achieved, including viral life history strategies that result in low rates of within-host evolution, or the establishment of a 'germline' lineage of viruses that avoids short-sighted evolution. These concepts provide a new perspective on the way in which some viruses have been able to establish and maintain global pandemics. On infection of a new host, the genomes of many viruses undergo rapid adaptive evolution, which may result in escape from host immune responses [1Foster T.L. et al.Resistance of transmitted founder HIV-1 to IFITM-mediated restriction.Cell Host Microbe. 2016; 4: 429-442Abstract Full Text Full Text PDF Scopus (124) Google Scholar, 2Murphy M.K. et al.Viral escape from neutralizing antibodies in early subtype A HIV-1 infection drives an increase in autologous neutralization breadth.PLoS Pathog. 2013; 9: e1003173Crossref PubMed Scopus (45) Google Scholar, 3Asquith B. et al.Inefficient cytotoxic T lymphocyte-mediated killing of HIV-1-infected cells in vivo.PLoS Biol. 2006; 4: e90Crossref PubMed Scopus (133) Google Scholar, 4Goonetilleke N. et al.The first T cell response to transmitted/founder virus contributes to the control of acute viremia in HIV-1 infection.J. Exp. 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Although these genetic changes make viruses superior competitors within their current host, they do not necessarily favour improved transmission between hosts [1Foster T.L. et al.Resistance of transmitted founder HIV-1 to IFITM-mediated restriction.Cell Host Microbe. 2016; 4: 429-442Abstract Full Text Full Text PDF Scopus (124) Google Scholar, 10Deymier M.J. et al.Heterosexual transmission of subtype C HIV-1 selects consensus-like variants without increased replicative capacity or interferon-α resistance.PLoS Pathog. 2015; 11: 1-22Crossref Scopus (65) Google Scholar, 11Honegger J.R. et al.Loss of immune escape mutations during persistent HCV infection in pregnancy enhances replication of vertically transmitted viruses.Nat. Med. 2013; 19: 1529-1533Crossref PubMed Scopus (52) Google Scholar]. A logical consequence of this process is 'short-sighted' evolution (see Glossary), by which adaptation at the within-host level occurs at the expense of the spread of the virus through the host population [12Levin B.R. Bull J.J. Short-sighted evolution and the virulence of pathogenic microorganisms.Trends Microbiol. 1994; 2: 76-81Abstract Full Text PDF PubMed Scopus (243) Google Scholar]. Susceptibility to short-sighted evolution will be influenced by two factors: the rate of viral adaptive evolution and the time between transmission events, which we refer to here as the 'transmission interval'. For instance, acute viral infections, such as influenza and norovirus, are typically short-lived with little time for within-host adaptation before transmission to a new host. Their strategy is one of 'smash and grab': infect a new host, reproduce, and get out before the adaptive immune system removes the infection. Such viruses have short transmission intervals and will exhibit little short-sighted evolution, irrespective of their rate of adaptive evolution. Alternatively, persistent viral infections that use proof-reading polymerases, such as Herpes and Papilloma viruses, are unlikely to suffer short-sighted evolution for a different reason; their low mutation rates constrain the rate of host-specific viral adaptation, regardless of their transmission interval (Figure 1). It is common for these viruses to have larger genomes with many genes, which enable the virus to manipulate or hide from host immune responses, for example by persisting in a nonproliferative latent state [13Duffy S. et al.Rates of evolutionary change in viruses: patterns and determinants.Nat. Rev. Genet. 2008; 9: 267-276Crossref PubMed Scopus (1096) Google Scholar]. In contrast, short-sighted evolution could be problematic for persistent chronic viral infections that use low-fidelity polymerases and which undergo active replication throughout infection, such as human immunodeficiency virus (HIV-1) and hepatitis C virus (HCV). High rates of mutation during replication, large viral population sizes, and long durations of infection combine to create considerable potential for within-host adaptation, enabling these viruses to outpace natural and induced immune responses. However, long transmission intervals mean that this adaptation may come at a cost of reduced transmissibility later in infection (Figure 1). Chronic viral infections are clearly successful within their natural hosts, so how do those with long transmission intervals avoid the detrimental impacts of short-sighted evolution? Here we suggest that such viruses exhibit life histories that either (i) significantly reduce rates of within-host adaptation, or (ii) lead to the retention of a genetic archive of viruses that are similar to the founder strains that initiated the infection. This archive is analogous to the germline in multicellular animals, which does not carry somatic mutations that accumulate during the lifetime of an individual. We further speculate that mechanisms that limit the effects of short-sighted evolution in chronic viruses could themselves be under viral control and therefore subject to selection (Box 1).Box 1Optimal Investment in a Viral GermlineWe construct an idealised mathematical model that can capture investment by a virus into a nonreplicating viral germline compartment, representing, for example, the HIV viral reservoir, or the proviral population of HTLV-1. We consider a viral infection comprising 1 unit of virus particles at the moment that allocation to the viral germline is decided, a proportion 1-μ of which are wild type and a proportion μ having a locally-adapted, mutant genotype – for example, a cytotoxic T-lymphocyte (CTL) escape mutation. A fraction γ of the virus particles are sequestered into the germline compartment, where they do not replicate, and the rest remain in the active compartment in which there is turnover of replicating viral particles, with the mutant viruses replicating at 1+σ times the rate of the wild-type viruses, but no net growth in the overall size of the viral population. We make the assumption of no net growth since, after the first few weeks of infection, viral loads tend to remain approximately stable for the majority of the infection. After a period of time, T, the wild-type virus particles transmit to new hosts, with each virus particle in the germline enjoying a fraction τ of the successful transmission enjoyed by those in the active compartment. The mutant virus particles have an unspecified rate of transmission that is lower than that of the wild type.The total transmission achieved by the infection's wild-type virus particles is therefore proportional to w = γ(1–μ)τ + (1–γ)(1–pT), where pT is the proportion of virus particles that are of the mutant type in the active compartment at time T. The first term represents the contribution of wild-type virus from the germline, and the second term is the contribution from the active compartment. The dynamics of the proportion pt of mutant particles in the active compartment, over the course of the infection, are given by dpt/dt = σpt(1–pt) (see [94Otto S.P. Day T. A Biologist's Guide to Mathematical Modelling in Ecology and Evolution. Princeton University Press, 2007Google Scholar] equation 3.11b for a derivation). Setting p0 = μ, this yields pT = (μ exp(σT))/(1+μ(exp(στ)–1)). Wild-type transmission success w is an appropriate measure of Darwinian fitness if the transmission ability of the mutant is sufficiently low that it does not completely displace the wild type from the wider population. This is because any mutant virus particles that do successfully transmit nevertheless enjoy zero long-term reproductive value [95Fisher R.A. The Genetical Theory of Natural Selection. Clarendon Press, 1930Crossref Google Scholar]: owing to the assumed absence of back mutation, all virus particles ultimately derive from wild-type ancestry, and hence no mutant virus particle leaves any descendants in the long term. Accordingly, any transmission achieved by mutant virus particles does not contribute to an infection's fitness.Natural selection favours an increase in allocation to the germline γ if dw/dγ > 0, which is equivalent to τ > 1/(1+μ(exp(σT)–1)). Denoting the right-hand side of the condition τ* yields a threshold level of germline transmission above which allocation to the germline is favoured, and below which it is not. Specifically, since the condition for increase is independent of the value of γ, natural selection favours full investment into the germline when the condition is satisfied (γ* = 1 when τ > τ*) and favours zero investment into the germline when the condition is not satisfied (γ* = 0 when τ < τ*). The threshold level of germline transmission τ* is a monotonically decreasing function of mutation rate μ, mutant replicative advantage σ, and time to transmission T (Figure I), such that increasing the values of these three parameters (and increasing the level of germline transmission, τ) makes it more likely that the germline will be favoured by natural selection.For example, if only a short period of replication occurs prior to transmission (small T, left-hand side of each panel in Figure I), then allocation to the germline is only favoured if transmission from the germline is high (large τ*), whereas a longer period of replication prior to transmission (large T, right-hand side of each panel in Figure I) means that allocation to the germline can be favoured even if transmission of wild-type virus from the germline is greatly impaired (small τ*). We construct an idealised mathematical model that can capture investment by a virus into a nonreplicating viral germline compartment, representing, for example, the HIV viral reservoir, or the proviral population of HTLV-1. We consider a viral infection comprising 1 unit of virus particles at the moment that allocation to the viral germline is decided, a proportion 1-μ of which are wild type and a proportion μ having a locally-adapted, mutant genotype – for example, a cytotoxic T-lymphocyte (CTL) escape mutation. A fraction γ of the virus particles are sequestered into the germline compartment, where they do not replicate, and the rest remain in the active compartment in which there is turnover of replicating viral particles, with the mutant viruses replicating at 1+σ times the rate of the wild-type viruses, but no net growth in the overall size of the viral population. We make the assumption of no net growth since, after the first few weeks of infection, viral loads tend to remain approximately stable for the majority of the infection. After a period of time, T, the wild-type virus particles transmit to new hosts, with each virus particle in the germline enjoying a fraction τ of the successful transmission enjoyed by those in the active compartment. The mutant virus particles have an unspecified rate of transmission that is lower than that of the wild type. The total transmission achieved by the infection's wild-type virus particles is therefore proportional to w = γ(1–μ)τ + (1–γ)(1–pT), where pT is the proportion of virus particles that are of the mutant type in the active compartment at time T. The first term represents the contribution of wild-type virus from the germline, and the second term is the contribution from the active compartment. The dynamics of the proportion pt of mutant particles in the active compartment, over the course of the infection, are given by dpt/dt = σpt(1–pt) (see [94Otto S.P. Day T. A Biologist's Guide to Mathematical Modelling in Ecology and Evolution. Princeton University Press, 2007Google Scholar] equation 3.11b for a derivation). Setting p0 = μ, this yields pT = (μ exp(σT))/(1+μ(exp(στ)–1)). Wild-type transmission success w is an appropriate measure of Darwinian fitness if the transmission ability of the mutant is sufficiently low that it does not completely displace the wild type from the wider population. This is because any mutant virus particles that do successfully transmit nevertheless enjoy zero long-term reproductive value [95Fisher R.A. The Genetical Theory of Natural Selection. Clarendon Press, 1930Crossref Google Scholar]: owing to the assumed absence of back mutation, all virus particles ultimately derive from wild-type ancestry, and hence no mutant virus particle leaves any descendants in the long term. Accordingly, any transmission achieved by mutant virus particles does not contribute to an infection's fitness. Natural selection favours an increase in allocation to the germline γ if dw/dγ > 0, which is equivalent to τ > 1/(1+μ(exp(σT)–1)). Denoting the right-hand side of the condition τ* yields a threshold level of germline transmission above which allocation to the germline is favoured, and below which it is not. Specifically, since the condition for increase is independent of the value of γ, natural selection favours full investment into the germline when the condition is satisfied (γ* = 1 when τ > τ*) and favours zero investment into the germline when the condition is not satisfied (γ* = 0 when τ < τ*). The threshold level of germline transmission τ* is a monotonically decreasing function of mutation rate μ, mutant replicative advantage σ, and time to transmission T (Figure I), such that increasing the values of these three parameters (and increasing the level of germline transmission, τ) makes it more likely that the germline will be favoured by natural selection. For example, if only a short period of replication occurs prior to transmission (small T, left-hand side of each panel in Figure I), then allocation to the germline is only favoured if transmission from the germline is high (large τ*), whereas a longer period of replication prior to transmission (large T, right-hand side of each panel in Figure I) means that allocation to the germline can be favoured even if transmission of wild-type virus from the germline is greatly impaired (small τ*). To begin, we outline the evidence that within-host adaption can reduce viral transmissibility. We then discuss mechanisms by which viruses may avoid short-sighted evolution, before examining the evidence that, in rapidly evolving viruses, germline lineages are preferentially transmitted. Because they have been much more widely studied, most of the examples we use come from viruses that infect humans, but the general principles apply to all viruses. Short-sighted evolution occurs when within-host adaptation reduces viral spread among hosts, either by reducing the per-contact transmissibility of the virus, or by reducing the contact rate of infected hosts due to increased pathogenicity, including host death. Here, we summarise the evidence for the accumulation of viral mutations during chronic infections that not only confer fitness advantages within hosts, but also limit the ability to transmit among hosts. The host environment presents a shifting landscape of selection pressures, created by a dynamic immune response and changes in the availability of target cells. Viral adaptation to these changes may result in short-sighted evolution. Unsurprisingly, most evidence for the loss of transmissibility following within-host adaptation comes from HIV-1. In the bid to develop a vaccine, there has been intense interest in characterising the viruses that are successfully transmitted and which initiate new infections (so-called transmitted/founder, or TF, viruses). Crucially, many of the characteristics of TF viruses appear to be selected against during the course of infection. Perhaps the most frequently cited of these is the switch from using the CCR5 to the CXCR4 coreceptor during late-stage infection in some patients, enabling the virus to infect naïve CD4+ T cells; in late infection there is a fall in the number of activated CD4+ CCR5+ T cells that can support highly productive viral infection, making it advantageous for the virus to infect naïve CD4+ CXCR4+ T cells, even though infection of these cells is less productive (reviewed in [14Swanstrom R. Coffin J. HIV-1 pathogenesis: the virus.Cold Spring Harb. Perspect. Med. 2012; 2: a007443Crossref PubMed Scopus (79) Google Scholar]). However, CXCR4 viruses are rarely transmitted, probably because their between-host transmissibility is severely diminished, although a competing explanation for the lack of CXCR4 TF viruses is simply because they are uncommon in the donor population [15Chalmet K. et al.Presence of CXCR4-using HIV-1 in patients with recently diagnosed infection: correlates and evidence for transmission.J. Infect. Dis. 2012; 205: 174-184Crossref PubMed Scopus (67) Google Scholar, 16Frange P. et al.Sexually-transmitted/founder HIV-1 cannot be directly predicted from plasma or PBMC-derived viral quasispecies in the transmitting partner.PLoS One. 2013; 8: e69144Crossref PubMed Scopus (14) Google Scholar]. Another well established characteristic of HIV-1 TF viruses is the reduced number of N-linked glycosylation sites encoded by the env gene compared to viruses circulating during later chronic infection (reviewed in [17Joseph S.B. et al.Bottlenecks in HIV-1 transmission: insights from the study of founder viruses.Nat. Rev. Microbiol. 2015; 13: 414-425Crossref PubMed Scopus (138) Google Scholar]). It is hypothesised that heavy glycosylation evolves during the course of infection because it increases viral resistance to neutralising antibodies [18Wei X. et al.Antibody neutralization and escape by HIV-1.Nature. 2003; 422: 307-312Crossref PubMed Scopus (2054) Google Scholar], but is detrimental at the point of transmission because viruses are more easily trapped or inhibited by agents in the transmission fluid, and/or are more likely to be targeted by the innate immune system. Other characteristics of HIV-1 TF viruses include high densities of the Env protein compared to viruses circulating during later infection. This might increase infection of cells in the genital tract and enhance binding to dendritic cells, thereby enabling efficient transport of the virus from the genital tract to the gut (reviewed in [17Joseph S.B. et al.Bottlenecks in HIV-1 transmission: insights from the study of founder viruses.Nat. Rev. Microbiol. 2015; 13: 414-425Crossref PubMed Scopus (138) Google Scholar], although a recent study of transmission pairs gives more equivocal results [19Iyer S.S. et al.Resistance to type 1 interferons is a major determinant of HIV-1 transmission fitness.Proc. Natl. Acad. Sci. U.S.A. 2017; 114: E590-E599Crossref PubMed Scopus (104) Google Scholar]). A recent detailed study of eight transmission pairs suggests that TF viruses are resistant to type-1 interferons, and that this feature correlates with high particle infectivity and ability to replicate [19Iyer S.S. et al.Resistance to type 1 interferons is a major determinant of HIV-1 transmission fitness.Proc. Natl. Acad. Sci. U.S.A. 2017; 114: E590-E599Crossref PubMed Scopus (104) Google Scholar]. In contrast to TF viruses, isolates from chronically infected donors were generally interferon sensitive, suggesting that HIV-1 within-host adaptation results in increased susceptibility to restriction by innate immune responses. In support of this, a recent report indicates that TF viruses are resistant to interferon-induced transmembrane proteins (IFITMs), which are believed to restrict cell entry of various viruses, including HIV-1 [1Foster T.L. et al.Resistance of transmitted founder HIV-1 to IFITM-mediated restriction.Cell Host Microbe. 2016; 4: 429-442Abstract Full Text Full Text PDF Scopus (124) Google Scholar]. However, within the first 6 months of infection neutralising antibody responses select for specific escape mutations in HIV-1 Env that result in susceptibility to IFITMs [1Foster T.L. et al.Resistance of transmitted founder HIV-1 to IFITM-mediated restriction.Cell Host Microbe. 2016; 4: 429-442Abstract Full Text Full Text PDF Scopus (124) Google Scholar]. Taken together, these reports suggest that within-host adaptation to adaptive immune responses increase the sensitivity of HIV-1 to interferon-stimulated genes, which in turn is detrimental to onward transmission. Transmissibility-reducing adaptations that have evolved in response to adaptive immune responses occur in other chronic viruses. During chronic hepatitis B virus (HBV) infection, viral variants that do not produce HBeAg antigen often emerge, which is likely driven by the appearance of anti-HBeAg antibody responses and/or enhanced cytotoxic T lymphocyte (CTL) killing of HBeAg-positive cells [20Mason W.S. et al.Immune selection during chronic hepadnavirus infection.Hepatol. Int. 2008; 2: 3-16Crossref PubMed Scopus (28) Google Scholar, 21Frelin L. et al.A mechanism to explain the selection of the hepatitis e antigen-negative mutant during chronic hepatitis B virus infection.J. Virol. 2009; 83: 1379-1392Crossref PubMed Scopus (66) Google Scholar]. Although HBeAg is dispensable for ongoing infection, it is important for the establishment of immmunotolerance in neo/antenatal infections [22Kramvis A. The clinical implications of hepatitis B virus genotypes and HBeAg in pediatrics.Rev. Med. 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The necessity to escape or avoid the host adaptive immune response can result in the accumulation of CTL and/or antibody escape mutations that are tailored to the specific host genotype, such as human leukocyte antigen (HLA) type. Whilst these mutations will be advantageous in the current individual, evidence suggests that antigenic escape in HIV-1, HCV, and HBV can have substantial fitness costs when measured in the absence of specific immune responses [25Seki S. Matano T. CTL escape and viral fitness in HIV/SIV infection.Front. Microbiol. 2012; 2: 1-5Crossref Scopus (8) Google Scholar, 26Kwei K. et al.Impaired virion secretion by hepatitis B virus immune escape mutants and its rescue by wild-type envelope proteins or a second-site mutation.J. 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Med. 2004; 10: 282-289Crossref PubMed Scopus (714) Google Scholar]. Third, the frequency of CTL escape mutations that carry a large cost is proportional to the frequency of the corresponding HLA alleles in the host population, but CTL escape mutations with little or no cost tend to accumulate at the population level [30Kawashima Y. et al.Adaptation of HIV-1 to human leukocyte antigen class I.Nature. 2009; 458: 641-645Crossref PubMed Scopus (373) Google Scholar]. A study looking at maternal transmission of HCV is also supportive of a transmission bias: transient immunodeficiency during pregnancy relaxes the selection pressure on HCV CTL escape variants, enabling the emergence of viruses that do not harbour these escape mutations. It is these viruses that preferentially transmit from mother to child, rather than the variants carrying CTL escape mutations specific to the mother [11Honegger J.R. et al.Loss of immune escape mutations during persistent HCV infection in pregnancy enhances replication of vertically transmitted viruses.Nat. Med. 2013; 19: 1529-1533Crossref PubMed Scopus (52) Google Scholar]. At the within-host level, mutations that enhance viral competitive ability will have a selective advantage. If these mutations also increase transmission they will rapidly spread throughout the viral population at the epidemiological level, as was observed during the 2014/15 West Africa Ebola outbreak [31Bedford T. Malik H.S. Did a single amino acid change make Ebola virus more virulent?.Cell. 2016; 167: 892-894Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar]. However, within-host adaptive mutations can increase the pathogenicity (virulence) of viruses, and if this results in fewer potential transmission events then within-host viral adaptation will reduce overall rates of transmission (even if transmissibility per contact is increased). Perhaps the clearest example of this is found in bovine viral diarrhoea virus (BVDV), a pestivirus of cows. Although BVDV can cause acute infection when transmitted horizontally, persistent infection can be established only via vertical in utero transmission; persistently infected animals are thought to be es
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