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Virus-Host Evolution and Positive Selection

Lucie Etienne*CIRI, Centre International de Recherche en Infectiologie, INSERM U1111 – CNRS UMR5308 – Université Lyon 1 – ENS deLyon, Lyon, France

Definition

Viruses, including HIV-like viruses, have been infecting primates and other hosts for millions of years.During this long-term common history, viruses and hosts have constantly put pressure on each other forsurvival. Over time, hosts have evolved first lines of defense against viruses, the cellular restrictionfactors, while pathogens have developed mechanisms of evasion and antagonism. These antagonisticrelationships have set up genetic conflicts between viruses and hosts that drive their evolution andinteractions. Therefore, over evolutionary time and as a result of virus-host arms races, host restrictionfactors have been rapidly evolving and display signatures of positive selection, in particular at the virus-host interface.

Introduction

Lentiviruses are retroviruses that have been infecting various mammals and in particular primates formillions of years (Gifford 2012). The virus responsible for the AIDS (acquired immune deficiencysyndrome) pandemic in humans, HIV (human immunodeficiency virus), has originated from cross-species transmissions of simian immunodeficiency viruses, SIVs, from non-human primates (Sharp andHahn 2011). Recent studies using various temporal markers and strategies have estimated that ancestorsof the modern-day lentiviruses existed in primates more than 10 million years ago (Compton et al. 2013).The long-term antagonistic coevolution of lentiviruses with their primate hosts has set up an evolutionaryarms race between the two adversarial entities. These ancient genetic conflicts can notably be witnessedtoday by signatures of positive selection in the host genome as a result of constant innovations at the virus-host interface. Understanding these long-term virus-host evolutions help in understanding current virus-host interactions and host susceptibility to modern-day pathogenic viruses.

Hosts have Evolved Specialized Genes, the Cellular Restriction Factors, toBlock Viral Replication

Cellular restriction factors are host proteins from the innate immune system that potently block viralreplication. These antiviral proteins target many stages of the viral life cycle, they may have differentmechanisms of viral inhibition that can be direct or indirect, and some are broadly acting while others arevery specific to a virus or a viral protein. Despite this diversity of antiviral function, restriction factorsshare a common evolutionary feature: restriction factors are immune genes that are rapidly evolving anddisplay signatures of positive selection as a result of genetic conflicts with pathogens (Duggal andEmerman 2012).

*Email: [email protected]

Encyclopedia of AIDSDOI 10.1007/978-1-4614-9610-6_373-1# Springer Science+Business Media New York 2015

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In lentiviral infection, cellular restriction factors play a key role in host susceptibility and pathogenesis.Although there is currently no strong evidence that restriction factors control viral replication of HIV inhumans, they may be a first line of defense and protect a host species against the emergence of newlentiviruses. Examples of restriction factors with anti-lentiviral activity include: APOBEC3G(apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3G), a cytidine deaminase thattargets the reverse transcription step of HIV, TRIM5 (tripartite motif protein) that impairs viral uncoating,SAMHD1 (SAM domain and HD domain-containing protein 1) that blocks reverse transcription, andTetherin/BST-2 (bone marrow stromal antigen 2) that restricts viral budding.

Viruses have Evolved Means to Counteract Restriction Factors by Evasion orAntagonism

Because viruses are obligate intracellular pathogens, they have evolved means to evade or counteract hostrestriction factors to complete their life cycle.

Certain restriction factors directly target a viral protein to restrict viral replication. In these cases,viruses can escape from this restriction by avoiding to be recognized by the host protein, a mechanism ofevasion or escape. Viruses will therefore evolve very rapidly at the virus-host interface to evade hostrecognition by single amino acid changes or more complex evolutionary strategies such as recombination.Evasion is for example used by the capsid of lentiviruses to escape recognition from the restriction factorTRIM5 (see details below).

Viruses have also evolved antagonists to directly target the cellular restriction factors and counteracttheir action. This mechanism is largely used by lentiviruses. It is particularly efficient to antagonizecellular factors that target another viral protein constrained in its evolution or to antagonize restrictionfactors that do not directly target the virus (i.e., indirect restriction). Indeed, several cellular restrictionfactors broadly block viruses by restricting steps of viral replication that are common to several virusfamilies. For example, host factors can restrict several viruses by decreasing the level of nucleic acids incells necessary for viral replication, inhibiting viral budding, recognizing viral RNA in the cytoplasm, orinhibiting mRNA translation. Viral antagonists are therefore specialized viral proteins that can interactwith cellular restriction factors and inhibit their action, often by inducing their proteasomal degradation,relocalizing them to a different compartment, producing competitive inhibitors by mimicry, or using otherfunctional inhibition mechanisms. The lentiviral antagonists are mainly encoded by viral accessory genesthat are not strictly necessary for replication and therefore bear more plasticity. For example, the accessoryproteins Vpr and Vpx antagonize SAMHD1, the accessory protein Vif counteracts APOBEC3G and otherAPOBEC3 proteins, and the viral proteins Vpu, Nef, or Env antagonize Tetherin/BST-2.

Adversarial Virus-Host Interactions Set Up a Genetic Conflict

These antagonistic relationships between the host and the virus proteins set up an evolutionary geneticconflict between the two entities (Daugherty and Malik 2012). This genetic battle is often referred as a“virus-host arms race,” which follows the Red Queen hypothesis where organisms constantly evolve andadapt to survive in an ever-changing environment (Van Valen 1973). Indeed, when a host protein restrictsa virus, it puts pressure by natural selection on the virus to evolve and evade or counteract the host proteinin order to complete its viral cycle. As a result, the “successful virus” is the one with changes that allow thepathogen to win the virus-host battle. In response to the new selection exerted by the virus, the host will inturn evolve and adapt to re-gain antiviral capacity. Over evolutionary times, these recurrent cycles of rapid


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virus-host evolution leave signatures of positive selection in both the virus and the host genome, inparticular at sites of interactions (Fig. 1). The primate restriction factors capable of blocking lentiviruses,such as APOBEC3G, SAMHD1, TRIM5, or Tetherin/BST-2, all bear signatures of positive selection.Furthermore, the identification of the specific sites that are under strong positive selection within the genehas powerfully aided the discovery of virus-host interacting domains and the characterization of hostprotein functions (Daugherty and Malik 2012).

Fig. 1 Long-term viral-host genetic conflict. Virus and host proteins are engaged into a “Red Queen” conflict inducing rapidadaptive evolution of the host antiviral gene over evolutionary time. This leaves signatures of positive selection in the hostgenome, in particular at the virus-host interface. Steps: The viral protein is able to antagonize the restriction factor (i.e., the“virus wins”). This puts a selective pressure on the host that will evolve and evade the antagonist, leading to a situation wherethe “host is winning.” Such selective pressure will, in turn, induce a rapid viral evolution and only viruses able to block the newhost protein will be selected. These virus-host interactions therefore set up unceasing evolutionary arms races. R.F. restrictionfactor. Black stars and triangles within genes represent amino acid changes. Dashed lines represent loss of block


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Host Evolutionary Analyses of Long-Term Virus-Host Genetic Conflicts:Methods to Analyze Positive Selection

Evolutionary analyses of the host genome may be performed to discover which host genes have beenunder genetic conflict and identify potential virus-host interfaces. During a viral-host arms race, changesthat result in a fitness gain are frequently due to mutations that result in amino acid changes. Therefore, atsites of virus-host interaction, a greater likelihood of non-synonymous substitutions (changes of aminoacids; dN) are observed over synonymous changes (changes in nucleotides that conserve amino acids;dS), which is a signature of positive selection. The estimation of the dN/dS ratio,o, can be used to identifysuch sites of adaptive evolution. Positive selection is characterized by dN/dS > 1, while purifying andneutral selection (characteristics of most host genes) are characterized by dN/dS < 1 and dN/dS = 1,respectively. Because the antagonistic virus-host evolution has been ongoing for million years, one canuse orthologous gene sequences from host species that have diverged millions of years ago to reconstructancestral gene sequences and infer the dN/dS ratio. Studies of primate phylogeny are therefore ideal tounderstand the viral-host arms races that have been ongoing in the primate lineage, including in theancestors of humans. The analyses of where and when the virus-host genetic conflicts have occurredimprove our understanding of the current viral epidemic, pathogenesis, and evolution.

Several statistical methods exist to detect such adaptive evolution (Pond et al. 2005; Yang 2007;Delport et al. 2010); a summary of the most commonly used tools is given here. First, to identify overallsignature of positive selection, one can estimate the dN/dS ratio across the gene using PARRIS fromHYPHY/Datamonkey or Codeml from the PAML package. Second, to identify specific sites evolvingunder strong positive selection, one can estimate the dN/dS ratio at individual sites along a gene (i.e., site-by-site selection analyses) using MEME from HYPHY/Datamonkey or BEB from PAML. Third, toidentify lineage-specific selection (i.e., episodic selection), one can estimate the dN/dS ratio for eachlineage, using Branch-REL from HYPHY/Datamonkey or the “free-ratio model” from PAML.

Examples of Major Virus-Host Genetic Conflicts in Lentiviral Infection

Several genetic conflicts between cellular restriction factors and lentiviral proteins have been character-ized in recent years. The main ones are summarized in Table 1 and some are further described here asexamples.

APOBEC3G (and Other APOBEC3 Members) and the Viral Protein VifIn early 2000s, the HIV-1 accessory protein Vif was found to be necessary for efficient HIV infection inprimary human cells and certain cell lines (Sheehy et al. 2002). Several studies then characterized that Vifwas allowing viral replication by inhibiting a cellular factor called APOBEC3G (Malim and Bieniasz2012). APOBEC3G is a member of the APOBEC3 gene family that is constitutively expressed in manycell types. APOBEC3G primarily restricts lentiviral replication by being incorporated in nascent virionsand deaminating cytidine to uracil in single-stranded viral DNA during reverse transcription, therebyinducing lethal G-to-A hypermutation in the viral genome. In turn, the viral antagonist Vif has the capacityto bind host APOBEC3G and the Cul5-EloBC ligase complex, targeting the cellular factor forproteasomal degradation. This antagonistic function of Vif is essential for lentiviral infection as it hasbeen retained in all extent primate lentiviruses and is therefore one of the most studied viral-host armsraces. Because no crystal structure of the complex has been solved yet, the interaction between Vif andAPOBEC3G has only been studied through mutational screens and evolutionary analyses. The analysesof positive selection as well as of the inter-species variations in the host gene have therefore aided our


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understanding of this ancient and ongoing genetic conflict (reviewed in: (Duggal and Emerman 2012)).The viral protein Vif is further the antagonist of other APOBEC3 protein members (i.e., APOBEC3D,APOBEC3H, and APOBEC3F) that also have anti-lentiviral activities. Vif is thereby involved in multipleviral-host arms races against several cellular proteins (Desimmie et al. 2014).

Tetherin/BST-2 and the Viral Proteins Vpu, Nef, and EnvTetherin/BST-2 inhibits viral infection by primarily blocking the release of enveloped viruses. This hosttransmembrane protein, stimulated by interferon, tethers budding virions to the plasma membrane,thereby blocking their release and inhibiting infection of a new target cell (Sauter et al. 2010). Recentstudies have shown that Tetherin is involved more broadly in viral immune sensing and activation of thehost innate immune response (Hotter et al. 2013). Lentiviruses have therefore evolved antagonisticmechanisms to counteract Tetherin activity and allow an efficient spread of viral particles betweencells. Primate lentiviruses have evolved different antagonists to inhibit Tetherin. HIV-1 encodes theVpu accessory protein that targets the transmembrane domain of Tetherin, downregulates it from thecell surface, and allows efficient viral release. On the other hand, most primate lentiviruses antagonizeTetherin by encoding a Nef protein that targets the cytoplasmic tail of Tetherin and impairs its traffickingto the plasma membrane. In contrast, HIV-2 seems to use another viral protein, its envelope protein, tosequester Tetherin away from the plasma membrane (Sauter et al. 2010). Overall, Tetherin is targeted bylentiviral antagonists in several domains of the protein. Consistent with this, Tetherin is evolving underpositive selection across primates, and specific sites in both the transmembrane domain and the cytoplas-mic domain demonstrate signatures of positive selection (Lim et al. 2010). In addition, a five-amino aciddeletion in the transmembrane domain of Tetherin, a genetic innovation not detected by standard tests forpositive selection, has further played a role in the virus-host arms race in humans (more below).

SAMHD1 and the Viral Accessory Proteins Vpr and VpxSAMHD1 is a deoxynucleotide triphosphohydrolase that notably lowers the dNTP pool in the cytoplasmand blocks the reverse transcription step of lentiviruses in certain cell types (Laguette et al. 2011). As a

Table 1 Examples of major genetic conflicts between primate cellular restriction factors and lentiviral proteins

Cellular restrictionfactor

Viral evasion orantagonism Evidence (in the host genome) of

MechanismViralprotein Long-term genetic conflict

Ongoing or recentgenetic conflict

APOBEC3G Antagonism Vif Positive selection in primates Polymorphism* inAGMs and rhesusmacaques

APOBEC3D,APOBEC3H,APOBEC3F

Antagonism Vif Positive selection in primates. Gene family(duplication)

Polymorphism* inhumans

SAMHD1 Antagonism Vpr orVpx

Positive selection in primates Polymorphism* inAGMs

TRIM5a andTRIMcyp

Evasion Capsid Positive selection in primates. Gene fusionthat led to the creation of TRIMcyp

Polymorphism* in rhesusmacaques

Tetherin/BST-2 Antagonism Vpu,Nef, orEnv

Positive selection in primates Specific 5-aa deletion inthe human lineage

AGMs African green monkeys, aa amino acids, * polymorphism that impacts virus-host interaction or the host antiviral genefunction


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countermeasure, most lentiviruses encode for an antagonist, Vpr or Vpx, which binds to SAMHD1,recruits it to the Cul4/DCAF1/DDB1 ubiquitin ligase complex, and targets it for degradation.As expected, SAMHD1 has evolved under strong positive selection throughout primate evolution(Laguette et al. 2012; Lim et al. 2012; Spragg and Emerman 2013). The identification of two hot spotsof positively selected sites aided in the identification of two distinct virus-host interaction sites, demon-strating the power of an evolutionary approach to understand virus-host antagonism (Fregoso et al. 2013).Of note, HIV-1 does not encode any direct antagonist to SAMHD1. It is likely that HIV-1 and its ancestorsSIVcpz and SIVgor have lost this antagonistic function as a result of another evolutionary selectiveconstrain (Etienne et al. 2013) and have evolved other means, which remain to be discovered, toefficiently infect their hosts.

Host Evolutionary Analyses of Ongoing and/or Recent Virus-Host GeneticConflicts

On recent time scales, the analysis of the dN/dS ratio to look for evidence of positive selection in hostgenome is not appropriate as it relies on accumulation of significant numbers of mutations over time.Recent genetic conflicts can be witnessed by the presence of polymorphism within a host species wherethe amino acid changes functionally impact the virus-host interaction (Table 1). For example,APOBEC3G is polymorphic within African green monkey species and several amino acid changeswere found to impact Vif antagonism (Compton et al. 2012). Spragg and Emerman further identifiedgenetic variants of SAMHD1 in the African green monkey populations that resist viral antagonism(Spragg and Emerman 2013). Together, these studies show evidence of ongoing and/or recent geneticconflicts between African green monkeys and lentiviruses, in particular between the restriction factorsAPOBEC3G and SAMHD1 and the lentiviral antagonists Vif and Vpr, respectively.

To test whether adaptive selection has occurred in recent years within a species, analyses based on allelefrequency differences and variation of allele frequencies between populations can be performed. Themain statistical methods to detect the type of selection acting on recent genetic conflicts have beenreviewed by Quintana-Murci and Clark (2013) and are briefly listed here: FST statistics to identify alleledifferences between populations; Tajima’s D, Fay and Wu’s H test, and others to identify unusual allelefrequencies; HKA test to estimate reduction or excess in diversity.

Virus-Host Evolution: Beyond Positive Selection

On both ancient and recent time scales, host proteins can undergo different types of evolution as a result ofevolutionary arms races with pathogens.

First, selection to maintain polymorphism within a species, also known as balancing selection, can bethe result of frequency-dependent selection or heterozygote advantage. When a single antiviral protein isfacing multiple selective pressures (e.g., from different viruses), different haplotypes can be maintained inthe population to “keep up” in the virus-host arms race. Some of the best-known examples of genesevolving under balancing selection are theMHC (major histocompatibility complex) genes (Hughes andYeager 1998), which by maintaining multiple alleles can recognize a wide variety of pathogens. Varioushaplotypes may also provide a heterozygous advantage to the host where the virus is forced to adapt tomultiple alleles with various interfaces to replicate efficiently. Heterozygous African green monkeys thathave two alleles of APOBEC3G with different virus-host interfaces apply a strong adaptive constrain on


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the viral antagonist Vif that is “facing two battlegrounds” (Compton et al. 2012). This may ultimately beadvantageous to the host during lentiviral challenges (Fig. 2, Box 1).

Second, the duplication of antiviral genes may be another major evolutionary strategy for the host toremain competitive in the virus-host arms race. Indeed, multiple restriction factors are part of a genefamily that results from gene expansion by duplication. APOBEC3G is for example one gene of theAPOBEC3 family that comprises seven members in primates. Other examples of antiviral gene duplica-tions come from the TRIM family, the IFITM genes, or the Mx genes. The advantage to maintain severalgenes for the host may be seen as an extension of the heterozygous advantage (a) to target different type ofviruses (i.e., diversification of the offense) and/or (b) to provide multiple virus-host interfaces (i.e.,diversification of the defense). (a) For example, the Mx2 restriction factor, thanks to its N-terminal tail,can restrict HIVas opposed to Mx1, which cannot block HIV but can restrict influenza and other viruses(Busnadiego et al. 2014; Goujon et al. 2014). This gene duplication has= allowed the host to restrict verydifferent viral families (Fig. 2, Box 2B). (b) On the other hand, gene duplication can also benefit the hostevasion from a viral antagonist. For example, the different APOBEC3 proteins with anti-lentiviralactivities are targeted by the viral antagonist Vif at different protein interfaces, constraining strongly theviral protein evolution (Desimmie et al. 2014) (Fig. 2, Box 2A).

Third, genetic innovations, such as insertions (from insertion of few amino acids to entire gene fusion)and deletions, are other evolutionary strategies observed during viral-host arms race (Fig. 2, Box 3).Because these events include dramatic changes to the host genome, they are often deleterious and are lessfrequent than single amino acid changes. However, there are few instances where such events wereselected during evolution, as they may have provided a strong advantage to the host under a majorselective pressure from a pathogen. An example of deletion can be found in the evolution of BST-2/Tetherin, which lost five amino acids in its N-terminal domain in the human lineage specifically, possiblyas a result of a viral-host arms race with a lentiviral antagonist like Nef (Sauter et al. 2009; Lim et al. 2010)(Fig. 2, Box 3A). Examples of gene fusion in an antiviral gene can be found in several primate species(e.g., owl monkeys, Asian macaques), where convergent evolution has led to the generation of TRIMcypfusion proteins. The retrotransposition of CypA (cyclophilin A) downstream or within the TRIM5 gene inseveral primate lineages has led to various forms of TRIMcyp proteins. These fused restriction factorshave gained new antiviral specificities thanks to the capsid-binding properties of CypA (Malfavon-Borjaet al. 2013) (Fig. 2, Box 3B).

Beyond Restriction Factors: Arms Races Between Viruses and Other HostGenes

Amongst host genes, few bear signatures of rapid evolution as restriction factors do. However, becausethe virus interacts with numerous other host proteins, it has been recently proposed that host cofactors mayalso be evolving under positive selection as a result of viral pressure. Unlike restriction factors that are“specialized intrinsic immune genes,” host factors that are usurped by the virus for replication alsoperform essential cellular functions. Therefore, like most host proteins that are important for cellularphysiology processes, they are expected to be mostly conserved throughout evolution (i.e., evolve underpurifying selection). However, recent studies have highlighted that, despite this evolutionary constrain,host factors that are necessary for virus replication may also be evolving under recurrent positive selectionas a result of “host evasion” mechanisms. This was first shown in an elegant study for TfR1, which is areceptor for multiple viruses (Demogines et al. 2013), and it was recently shown that some HIV cofactorsmay also be under positive selection (Meyerson et al. 2014). For example, the HIV receptor CD4 is foundunder strong positive selection in primates and a site that is bearing a strong signature of positive selection


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Fig.2

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is implicated in the specificity of HIV entry (Meyerson et al. 2014). Therefore, even though most hostcofactors of HIV seem to be generally conserved, a subset of them may evolve under positive selectiondriven by virus-host interactions that have played out over evolutionary time. More evolutionary studiesof HIV cofactors associated with functional analyses will help in the characterization of these “unusual”viral-host arms-races and increase our understanding of the biology and evolution of these cellularcofactors that could be potential anti-HIV drug targets.

Consequences of Ancient and Ongoing Virus-Host Arms Races on the Cross-Species Transmission Potential of Modern-Day Lentiviruses

Ancient and ongoing virus-host arms races have therefore shaped modern-day host species and inparticular have driven the specificities of interactions between the host restriction factors and viruses.As viruses can adapt very rapidly to their host, modern-day viruses efficiently counteract the antiviralgenes of the host species they infect. However, differences in restriction factors between species may besufficient to create a barrier to viruses and may shape the host species spectrum of viruses (i.e., species-specificities). These differences between orthologous antiviral genes have mainly been shaped by ancientvirus-host genetic conflicts (Daugherty and Malik 2012; Duggal and Emerman 2012) and currentselective pressures continue to shape our antiviral repertoire. Therefore, the evolutionary history ofvirus-host interactions may in part explain the susceptibility and resistance of modern-day species toviral cross-species transmissions (Fig. 3). In particular, the differential susceptibility of host species tolentiviral cross-species transmissions may lie in the capacity of restriction factors to block SIVemergence(Fig. 3, first scenario). Furthermore, the evolutionary potential of a virus to adapt to the new restrictivecellular environment may determine the ease at which cross-species transmissions can occur (Fig. 3,second scenario).

Lentiviruses have infected primates over millions of years. However, the global picture today is thateach primate species is infected by its own lentiviral lineage and few cross-species transmissions havebeen identified. This lentiviral species-specificity may be driven by the inability of lentiviruses toantagonize or escape from the restriction factors encountered in a new species (Fig. 3, first scenario).Although the influence of host restriction factors on viral cross-species transmission has not been wellstudied, in particular in natural settings, some in vitro and in vivo experimental studies have tackled thisquestion. Both APOBEC3G and TRIM5 may represent natural selective barriers to lentiviral cross-species transmissions and only viruses that have the capacity to adapt rapidly to counteract or escapefrom the antiviral proteins will successfully emerge (Fig. 3, second scenario). Indeed, although the role ofAPOBEC3G as a species barrier has been mainly investigated in experimental cross-species transmis-sions, it has been shown that its evolution and its variability between and within primate species have beenimplicated in the species-specificity of lentiviruses (Johnson 2013). Studies on the origin of the HIV-1/SIVcpz lineage in hominoids also suggest that APOBEC3G has been a selective barrier for SIVs, and onlylentiviruses with some capacity to antagonize the new host APOBEC3G may have the potential to jumpefficiently in the new species (Etienne et al. 2013) (Etienne et al. unpub). Genetic variations in TRIM5may also influence in some primates the outcome of cross-species transmissions. Indeed, TRIM5 hasplayed a role of selective barrier at the origin of SIVmac during the species-jump of SIVsmm from sootymangabeys to macaques (Johnson 2013). Future studies on the role of other restriction factors as selective


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barriers and their potential hierarchy are likely to uncover more examples of host barriers to transmissionof lentiviruses among primates.

Fig. 3 Model for the consequences of long-term viral-host arms race on the potential of viral cross-species transmission.Steps: (a) The viral protein A is able to antagonize the restriction factor 1. This puts a selective pressure on the host that willevolve to evade the antagonist, leading to (b) where the “host is winning.” Such selective pressure will induce a rapid viralevolution. (c) Only viruses able to block the new host protein will be selected. (d) This virus-host interaction sets anevolutionary “arms-race” in the host species 1. Similarly, another evolutionary “arms-race” is in place in the host species2 infected by a virus B. So that, when a virus crosses from species 2 to species 1, the host will most likely “win” and this will, inmost cases, prevent the cross-species transmission (first scenario). However, if the virus is able to rapidly adapt to the newspecies, it will successfully jump the species barriers (second scenario)


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Conclusion

Over evolutionary time, primate species have been under the selective pressure of many pathogens,including lentiviruses. The adversarial interactions between the cellular restriction factors, principalcomponent of the host intrinsic immune system, and the viral antagonists have set the two entities in a“Red Queen” competition where the host gene imposes a selective pressure on viral replication and thevirus exerts pressure on the host for survival. These antagonistic virus-host interactions and evolutionshave therefore mainly evolved under positive selection, although other evolutionary strategies have beenidentified. In conclusion, both ancient and recent virus-host genetic conflicts have shaped our modern-dayintrinsic immune genes, largely determining our current sensitivity and resistance to pathogenic andemerging viruses.

Acknowledgment

LE is supported by an amfAR Mathilde Krim Fellowship in Basic Biomedical Research (108499-53-RKGN) and the Centre National de Recherche Scientifique (CNRS). Thank you to Molly Ohainle andKevin Tartour for their comments on the manuscript, the members of the Emerman and Malik Labs forhelpful discussions on these concepts.

Cross-References

▶APOBEC Family and Viral Restriction▶APOBEC3G▶Cell Intrinsic Immunity▶Cellular Restriction Factors▶ Fv1: Prototypical RF▶ IFN Signalling and Induction of Restriction Factors▶MHC Locus Variation▶Nef/Env/Vpu/Tetherin▶ SAMHD1▶Tetherin▶TRIM5a▶Vif/A3G▶Vpx/SAMHD1

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