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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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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 • Intrisicimmunityrefersto a setofconstitutivelyexpressedcellular-based anti-viral defensemechanismsspecificallytargetingeukaryotic RNA viruses.
(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 • 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/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 • 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 • 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 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 • 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
Summary of known intrinsic factors Marcello A. (2006) Retrovirology 3:7