Download Intrinsic immunity

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 cellularbased 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
Same, can become
saturated
Differentially
Response upon
Same
repeated infection
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 heteromultimers 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
integration complex (PIC)
pre-
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 speciesspecific 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
 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
(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