1. Evolutionary Biology
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Evolutionary conflicts and adverse effects of antiviral factors

  1. Daniel Sauter  Is a corresponding author
  2. Frank Kirchhoff  Is a corresponding author
  1. Institute of Molecular Virology, Ulm University Medical Center, Germany
  2. Institute of Medical Virology and Epidemiology of Viral Diseases, University Hospital Tübingen, Germany
Review Article
Cite this article as: eLife 2021;10:e65243 doi: 10.7554/eLife.65243
4 figures and 2 tables

Figures

Antiviral factors targeting components of the virus.

The retroviral replication is exemplarily shown to illustrate antiviral host factors (violet) that directly target viral proteins, nucleic acids, and membranes during essentially all steps of the viral life cycle. While some factors successfully distinguish between self (blue, right panel) and non-self (pink, left panel), others may have unintended side effects on the host as they also target cellular factors. CpG: cytosine guanine dinucleotides; dsRNA: double-stranded ribonucleic acid; CAP0: 5′ mRNA cap with unmethylated ribose hydroxy-groups; CAP1: 5′ mRNA cap with methylated ribose hydroxy-group; IRES: internal ribosome entry site; PPP: 5′-triphosphate group without cap; abbreviations of protein names are explained in the text.

Antiviral factors modulating virus-dependency factors.

Several antiviral host proteins (violet) suppress viral replication (left panel) by modulating the stability, localization, or activity of cellular factors (orange) involved in the viral replication cycle. Since these host factors also play important roles in the cell, their inhibition may be associated with detrimental side effects (right panel). dsRNA: double-stranded ribonucleic acid; tRNA: transfer ribonucleic acid; 25-HO-Chol.: 25-hydroxy-cholesterol; abbreviations of protein names are explained in the text.

Dual role of endogenous retroviruses (ERVs).

ERV-derived regulatory elements (promoters, enhancers, repressors, insulators) and proteins (syncytin-1, syncytin-2, suppressyn, etc.) may have beneficial (left) or detrimental (right) effects on the host. Abbreviations are explained in the text.

Long-term effects of antiviral proteins on host evolution.

Antiviral proteins (violet) exert selection pressure on host factors to limit similarities with viral factors. As a result, the emergence of antiviral cellular factors may be associated with constraints in host evolution.

Tables

Table 1
Selection of antiviral factors directly targeting viral replication (abbreviations are explained in the text).
Antiviral factor(s)Target(s)Discrimination between self and non-selfEffect on viral replication(Potential) Unwanted effects on host cell
ImmediateLong term
IFITMsFusing membranesMembrane curvature, lipid compositionImpaired fusion of viral and host membranesImpaired fusion of cellular membranesConstraints in membrane fusion (e.g. Syncytin-mediated trophoblast fusion)
SERINCsFusing membranesNot known (viral glycoprotein dependency?)Impaired fusion of viral and host membranesNone (?)
TRIM5α, Fv1Retroviral capsidsSpecific protein-bindingUntimely uncoatingNone (?)Constraints in the co-option of endogenous retroviral capsid proteins
KAP1Retroviral integraseSpecific protein-bindingInhibition of integrationNone
ZAP/TRIM25/ KHNYNRNACpG contentDegradation of viral RNADegradation of host RNACpG depletion (?)
RNAse LRNAdsRNA-dependent, OAS-mediated activationDegradation of viral RNADegradation of host RNAAvoidance of dsRNA
SAMHD1RNANot knownDegradation of viral RNADegradation of host RNA (?)
IFITsRNAIRES, modification of 5′ RNA ends (cap-1 vs. cap-0)Inhibition of viral translationInhibition of cellular translation (?)Depletion of IRES structures, constraints in mRNA capping
HERC5/ISG15Numerous viral proteins (e.g. HIV-1 Gag, HPV capsid)Preferred ISGylation of newly translated proteinsInhibition of viral protein functionInhibition of host protein function
TetherinBudding membranesLocalization in lipid raftsInhibition of virion releaseInhibition of exosome release, inhibition of cell division (?)
APOBECsssDNA, RNAPartially sequence dependentIntroduction of lethal hypermutations in the viral genomeEmergence of detrimental mutationsDepletion of specific dinucleotides
Table 2
Selection of antiviral factors indirectly targeting viral replication (abbreviations are explained in the text).
Antiviral factor(s)Target(s)Discrimination between self and non-selfEffect on viral replication(Potential) Unwanted effects on host cell
ImmediateLong term
IFITM3VAPA, OSBPMembrane curvature, lipid compositionImpaired fusion of viral and host membranesImpaired fusion of cellular membranesConstraints in membrane fusion (e.g. syncytin-mediated trophoblast fusion)
CH25HCholesterolNot knownImpaired fusion of viral and host membranes, impaired membraneous web formationImpaired fusion of host membranes (?)
SAMHD1dNTPsNot knownLimits reverse transcription/viral DNA replicationInhibition of host DNA replicationRegulation of SAMHD1 activity in dividing cells
MxBNucleoporinsSimultaneous interaction with viral (capsid) proteinsReduced nuclear import of subviral complexesImpaired nuclear pore transportEvolution of diverse nuclear pore variants
KAP1NuRD complex/HDACs, SETDB1, transcription factorsNot knownSuppression of viral gene transcription, latencySuppression of host gene transcription
TRIM22Sp1Not knownReduced Sp1-driven expression of viral genesReduced Sp1-driven expression of host genesConstraints in Sp1-driven gene expression
IFI16, MNDA, IFIXSp1Chromatinization status of the DNAReduced Sp1-driven expression of viral genesReduced Sp1-driven expression of host genesConstraints in Sp1-driven gene expression
PKReIF-2αActivation by dsRNAReduced translation of viral mRNAReduced translation of host mRNAAvoidance of dsRNA
IFITseIF3IRES, modification of 5′ RNA endsInhibition of translationInhibition of translation (?)Depletion of IRES structures, mRNA capping (methylated)
SLFN11tRNApreferred targeting of tRNAs exploited by virusesReduced translation of viral mRNAReduced translation of cellular mRNASpecific codon usage pattern
PAR1, GBP2, GBP5FurinNot knownImpaired furin-mediated maturation of viral (glyco)proteinsImpaired proteolytic activation of host proteinsConstraints in furin-mediated protein cleavage
HERC5/ISG15Numerous host proteins (e.g. IRF3, RIG-I, PKR)Preferred ISGylation of newly translated proteinsSeveral proposed inhibitory mechanismsModulation of host protein stability and function
ViperinFPPS,
CTP
Not knownInhibition of viral budding, inhibition of viral RNA polymerizationInhibition of cellular protein secretion and potentially cellular RNA synthesis

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