Reviewed by Christina Ziegler Intrinsic immunity: a front line defense against viral attack Paul D. Bieniasz Nature Immunology 2004 Reviewed by Christina Ziegler Oct 26th 2009

Relationship of intrinsic immunity with innate and adaptive immunity Intrisic immunity refers to a set of constitutively expressed cellular-based anti-viral defense mechanisms specifically targeting eukaryotic RNA viruses. Innate immunity Intrinsic immunity Adpative immunity Means of pathogen recognition Unspecific (PAMS) via TLRs or PRR Specific via certain residues/motives Antigen-specific receptors Consequence to recognition Responsive Constitutive Time until response Minutes to days Directly Days to weeks Response upon repeated infection Same Same, can become saturated Differentially

Overview of intrinsic antiviral effector mechanisms

(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 EIAV: Equine infectious anemia virus 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  Restrict replication of vif-deficient HIV strains Permissive cells T cell lines like e.g. SupT1, Jurkat, CEM-SS  Permit replication of vif-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 Cytidine deaminases irreversible catalyze the hydrolytic deamination of (d)cytidine to (d)uridine primates encode up to five APOBEC3 proteins (3A, B, C, F, G) In absence of HIV-1 Vif (viral infectivity factor), cytidine deaminases (esp. hA3G and hA3F) are packed into virions and catalyze deamination of dC to dU-residues during replication of ss proviral DNA  hypermutations and thus destabilisation of the viral genome (ii) interact with viral genome and attenuate viral replication hA3G and hA3F can theoretically target any virus those DNA replication occurs 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

Thank you for your attention!

Summary of known intrinsic factors Marcello A. (2006) Retrovirology 3:7