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 Responsive

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

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

(3) Deamination of viral RNA before reverse transcription

Non-Permissive cellsprimary T cells and macrophages T cell lines like e.g. H9, CEM

Restrict replication of vif-deficient HIV strains

Permissive cellsT 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 (i)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