Intrinsic immunity a front line defense against viral attack paul d bieniasz nature immunology 2004
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Reviewed by Christina Ziegler Oct 26 th 2009 PowerPoint PPT Presentation


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Intrinsic immunity: a front line defense against viral attack Paul D. Bieniasz Nature Immunology 2004. Reviewed by Christina Ziegler Oct 26 th 2009. Relationship of intrinsic immunity with innate and adaptive immunity.

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Reviewed by Christina Ziegler Oct 26 th 2009

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Intrinsic immunity a front line defense against viral attack paul d bieniasz nature immunology 2004

Intrinsic immunity: a front line defense against viral attackPaul D. BieniaszNature Immunology 2004

Reviewedby Christina Ziegler

Oct 26th 2009


Relationship of intrinsic immunity with innate and adaptive immunity

Relationship of intrinsic immunity with innate and adaptive immunity

  • Intrisicimmunityrefersto a setofconstitutivelyexpressedcellular-based anti-viral defensemechanismsspecificallytargetingeukaryotic RNA viruses.


Overview of intrinsic antiviral effector mechanisms

Overview of intrinsic antiviral effector mechanisms


1 receptor inference by endogenously expressed murine env prevents infection

(1) Receptor inference by endogenously expressed murine Env prevents infection

  • Late 1960s: Susceptibility traits in mice were discovered against infection with Friend strain of MLV

  • called Friend virus susceptibility (Fv) genes

  • Expression of Fv genes conferred resistance against MLV and thereby decreased frequency of leukemia

  • Fv4 encodes endogenous retroviral Env protein

  • receptor interference prevents viral entry and thus infection


2 inactive murine capsid hetero multimers prevent viral assembly

(2) Inactive murine capsid hetero-multimers prevent viral assembly

  • Fv1 is unique to the mouse and blocks infection to MLV only

  • Fv1 capsid-like restriction factor derived from retroviral Gag protein (cleaved into MA, CA and NC)

  • Resistance to MLV depends on allelic variant (Fv1n/n, Fv1b/b or Fv1n/b) and the MLV strain

  • Fv1 forms inactive heteromultimers with viral CA110 in the pre-integration complex (PIC)

Cone-shaped viral capsid is formed by CA hexamers.


Primates encode the capsid specific restriction factor ref1 trim5

Primates encode the Capsid-specific restriction factor Ref1/Trim5α

  • CA-specific lentiviral inhibitors were called Lv1 (lentiviral susceptibility factor 1)

  • In primates, the Lv1 homologue was named Trim5α (Tripartite interaction motif 5 splice variant alpha), previously known as Ref1 (restriction factor one) in humans

  • Unclear if Lv1 and Ref1/Trim5α are different entities or species-specific variants

  • Depending on the species of origin, Trim5α targets the retroviral CA before reverse transcription occurs

  • Possibly, Lv1 and Trim5α also interfere during trafficking of CA molecules


3 deamination of viral rna before reverse transcription

(3) Deamination of viral RNA before reverse transcription

  • Non-Permissive cells

  • primary T cells and macrophages

  • T cell lines like e.g. H9, CEM

  •  Restrictreplicationofvif-deficient HIV strains

  • Permissive cells

  • T cell lines like e.g. SupT1, Jurkat, CEM-SS

  •  Permit replicationofvif-deficient HIV strains

Non-permissive cells express a homolog of Cytidine deaminases called APOBEC3 (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3).


3 interference with viral reverse transcription

(3) Interference with viral reverse transcription

  • Cytidinedeaminases irreversible catalyzethehydrolyticdeaminationof (d)cytidineto (d)uridine

  • primatesencodeuptofiveAPOBEC3proteins (3A, B, C, F, G)

  • In absenceof HIV-1 Vif (viral infectivityfactor), cytidinedeaminases (esp. hA3G and hA3F) arepackedintovirionsand

  • catalyzedeaminationofdCtodU-residuesduringreplicationofssproviral DNA

  •  hypermutationsandthusdestabilisationofthe viral genome

  • (ii) interactwith viral genomeandattenuateviral replication

  • hA3G and hA3F cantheoreticallytargetanyvirusthose DNA replicationoccurs in cytoplasm


3 interference with viral reverse transcription1

(3) Interference with viral reverse transcription

  • Vif is a regulatory protein needed for productive infection in non-permissive cells

  • Able to recruit ubiquitination machinery and upon simultaneous binding, hA3G is targeted for proteosomal degradation

  • Degradation is incomplete potentially to enhance viral diversity


4 potenial other intrinsic factors

(4) Potenial other intrinsic factors

  • Expression of nuclear cytidine deaminases can potentially inhibit replication of RNA viruses replicating in nucleus

  •  requires high sequence specificity to prevent degradation of cellular RNAs

  •  Opportunity for viral escape

  • Zinc-finger antiviral proteins able to inhibit accumulation of cytoplasmic RNA likely by binding to AU-rich sequences and recruitment to exosome

  • Vpu-interfering cellular protein prevents Vpu (viral protein U)-dependent release of HIV-1 and thereby results in the formation of heterokaryons (multinucleated giant cells)

  • Possibly, other members of TRIM family have likewise antiviral functions

  • Concerted attack by multiple antiviral proteins most likely succeeds against (retro)viral infections .

  • Benficial if intrinsic immunity would target viral components/steps which unlikely generate escape mutants.


Sum of mechanisms exploid by the discussed factors of the intrinsic immunity

Sum of mechanisms exploid by the discussed factors of the intrinsic immunity


Thank you for your attention

Thank you for your attention!


Summary of known intrinsic factors

Summary of known intrinsic factors

Marcello A. (2006) Retrovirology 3:7


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