Literature Review Summer 2009
PART I: HDACs and Inflammation/cytokine response
Choi JC, Holtz R, Murphy SP. 2009. Histone Deacetylases Inhibit IFNgamma-Inducible Gene Expression in Mouse Trophoblast Cells. Journal of
Immunology 182(10): 6307-6315
- HDACs need to be looked at on an operon by operon basis; here HDAC
inhibitors are used to induce expression of genes regulated by interferon
gamma
Bode KA, Schroder K, Hume DA, et al. 2007. Histone deacetylase inhibitors
decrease Toll-like receptor-mediated activation of proinflammatory gene
expression by impairing transcription factor recruitment. Immunology 122(4):
596-606
- Perfomed on human and murine macrophages
- Histone acetylation allows for chromatin to assume a more open structure
(allowing for transcriptional activity)
- HDACi’s inhibited production of IL-12-p40
o Produced by DC’s, involved in differentiation of naïve T-cells,
stimulates production fo INF-gamma and TNF-alpha, activates NK
cells and CD8+ T-cells
- HDAC’s had no effect of upstream nf-kB or MAPK activation
Nusinzon I, Horvath CM. 2003. Interferon-stimulated transcription and innate
antiviral immunity require deacetylase activity and histone deacetylase 1.
PNAS 100(25): 14742-14747
- HDAC 1 associates with STAT1 and STAT 2 to activate transcription
- Inhibition of HDAC 1 by siRNA decreases INF-alpha responsiveness
o Does not act upstream of ISGF3 DNA binding
- Expression of HDAC 1 boosts the INF-alpha response
- Innate antiviral activity is inhibited in the absence of deacetyalse activity
o INF-gamma-STAT 1 system needs deacetylase activity
o STAT3 dependent transcription is inhibited by TSA
o IL-2 inhibited by TSA
Lucas JL, Mirshahpanah P, Haas-Stapleton E, et al. 2009. Induction of
Foxp3(+) regulatory T cells with histone deacetylase inhibitors. Cellular
Immunology 257(1-2):97-104
- SAHA and MS-275 (HDACi’s) induce generation of Tregs that display
suppressive activity against CD4+25- T proliferation.
- Treg generation may serve as a novel mechanism for HDACi regulation of
immune response
Wang LQ, Tao R, Hancock WW. 2009. Using histone deacetylase inhibitors to
enhance Foxp3(+) regulatory T-cell function and induce allograft tolerance.
Immunology and Cell Biology 87(3):195-202
- TSA promotes acetylation of Foxp3 itself
o Required for effective binding of foxp3 to promoter of IL-2
 IL-2 used for T cell development
 Foxp3 normally functions to suppress autoimmune T-cells
- HDACi’s that blocked class I AND class II HDACs were the only agents
that exhibited Treg suppression activity in vivo/ in vitro
Spange S, Wagner T, Heinzel T, et al. 2009. Acetylation of non-histone proteins
modulates cellular signalling at multiple level. International Journal of
Biochemistry and Cell Biology 41(1):185-198
- reversible lysine acetylation affects mRNA stability and the localization,
interactions, degredation and function of proteins
- HDACi’s also modulate post translational acetylation
Brown CR, Kennedy CJ, Delmar VA, et al. 2008. Global histone acetylation
induces functional genomic reorganization at mammalian nuclear pore
complexes. Genes and Development 22(5):627-639
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nuclear pores are large protein compelexes that cross the nuclear
envelope (about half are nuclear porins) allow for the transport of water
soluble molecules across nuclear envelope
nuclear localization of genes (in yeast) is tied to their transcriptional status
upon treatment with HDACs- extensive nuclear rearrangement
o generated from binding map of nuclear porin 93 (Nup 93)
o HDACs reorganization promotes differential recruiting regions of
transcriptional regulation to mammalilan nuclear pore complexes
Ryan CM, Harries JC, Kindle KB, et al. 2006. Functional interaction of CREB
binding protein (CBP) with nuclear transport proteins and modulation by
HDAC inhibitors. Cell Cycle 5(18):2146-2152
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Provides evidence for Interactions between CBP (histone
acetyltransferase) and nuclear transport proteins
o HDACi’s may regulate nucleo-cytoplasmic shuttling of importins
Recruitment of CBP to gene promoters results in chromatin modification,
mainly by acetylastion of lysine residues in histone N-terminal tails
Dokmanovic M, Marks PA. 2005. Prospects: Histone deacetylase inhibitors.
Journal of Cellular Biochemistry 96(2):293-304
- At high does: induce growth arrest, differentiation, apoptosis,
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autophagoctyic cell death
Expression of genes is in large part regulated to the structure of chromatin
proteins (epigenetic regulation)
Acetylation of histone lysine residues on histone tails is among the most
extensively studied aspects of chromatin structure
Article: different cell phenotypes induced by HDACi’s, why are normal
certain tumors more responsive to HDACis, what is basis of selectivity in
altering gene expression
Kramer OH, Knauer SK, Greiner G, et al. 2009. A phosphorylation-acetylation
switch regulates STAT1 signaling. Genes and Development 23(2): 223-235
- acetylation of STAT1 counteracts IFN-induced STAT phosphorylation,
nuclear translocation, DNA binding and target gene expression
- Overview of modulation of STAT 1 activity
Bosisio D, Vulcano M, Del Prete A, et al. 2008. Blocking T(H)17-polarizing
cytokines by histone deacetylase inhibitors in vitro and in vivo. Journal of
Leukocyte Biology 84(6):1540-1548
- Investigated the effects of HDACi’s on the maturation and activation of
human DC’s in the presence of INF-gamma and LPS (SAHA and TSA)
o Th1 and Th17 inducing cytokines IL-12 and IL-23
o Block Th1 attracting chemokines CXCL9, CXCL10, CXCL11
o HDACi’s = Immunomodulary at nonapoptotic doses
De Boer J, Licht R, Bongers M, et al. Inhibition of histone acetylation as a tool
in bone tissue engineering.Tissue Engineering 12(10): 2927-2937
- inhibition of HDAC’s stimulates osteoblast maturation
- negative impact on cell proliferation (human mesenchymal stem cells)
Kramer OH, Baus D, Knauer SK, et al. Acetylation of Stat1 modulates NFkappa B activity. Genes and Development. 20(4): 473-485
- both HDACi’s and INF-alpha alter equilibrium and induce STAT 1
acetylation; acetylated STAT 1 binds to NF-kB p 65, p65 binding, nuclear
localization and expression of anit-apoptotic genes decreases
o acetylation of STAT 1 regulates NF-kB and apoptosis
Halili MA, Andrews MR, Sweet MJ, et al. 2009. Histone Deacetylase Inhibitors
In Inflammatory Disease. Current Topics in Medicinal Chemistry. 9(3): 309-319
- HDAC and HAT are known to modify non-histone proteins to control
diverse cell processes
o Inflammation
 Activity of cytokines receptors
 Nuclear hormone receptors
 Intracellular signaling molecules
 Transcription factors
o HDACs as possible treatments of

Arthritis, inflammatory bowel disease, septic shock, asthma,
MS, CNS degeneration etc.
Han SB, Lee JK. 2009. Anti-inflammatory effect of Trichostatin-A on murine
bone marrow-derived macrophages. Archives of Pharmacal Research.
32(4):613-624
- compared effect of 5 differetnt HDACi’s ( on NO production of RAW 264.7)
- TSA significantly decreased mRNA and protein levels of TNF-alpha, IL-6,
IL-1 beta; pretreatment with TSA increased the level of
immunosuppressive IL-10
Hamalainen M, Lilja R, Kankaanranta H, et al. 2008. Inhibition of iNOS
expression and NO production by anti-inflammatory steroids Reversal by
histone deacetylase inhibitors. Pulmonary Pharmacology and Therapeutics.
21(2):331-339
- During inflammation NO is produced by iNOS (nitric oxide synthase)
o Induced by bacterial products and cytokines
- Studided the effects of HDACi’s (TSA, apicidin, MC1293) on suppressive
effects of glucocorticoids on NO production and iNOS expression
o Concluded that iNOS expression and NO production
Choi Y, Park SK, Kim HM, et al. 2008. Histone deacetylase inhibitor KBH-A42
inhibits cytokine production in RAW 264.7 macrophage cells and in vivo
endotoxemia model. Experimental and Molecular Medicine. 40(5):574-581
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examined HDACi (KBH-A42)
decreased expression of TNF-alpha, NO production, proinflammatory
cycle
o p38 kinase is involved in KBH-A42 inhibiiton
RT-PCR confirmed TNF-alpha, IL-1beta, IL-6 inhibition
NF-kB not directly changed, also phos. Of ERK1/2 and SPAK/JNK not
effected
Sailhamer EA, Li YQ, Smith EJ, et al. 2008. Acetylation: a novel method for
modulation of the immune response following trauma/hemorrhage and
inflammatory second hit in animals and humans. Surgery 144(2): 204-216
-
hemorrhage in animals produced severe shock and a pro-inflammatory
state
o SAHA normalizes TNFa levels
Rats responds to SAHA either with marked attenuation of exaggeration of
inflammatory cytokines
o Cytokines levels were independent of gene expression, implicating
acetylation of non-nuclear proteins as the dominant regulatory
mechanism
Li NN, Zhao D, Kirschbaum M, et al. 2008. HDAC inhibitor reduces cytokine
storm and facilitates induction of chimerism that reverses lupus in anti-CD3
conditioning regimen. PNAS 105(12): 4796-4801
-
in allogenic hematopoietic cell transplantation (HCT) anti-CD-3
conditioning is used to allow donor CD8+ T cells to facilitate engraftment
cytokine storm is produced by anti-CD3 conditioning regimine
SAHA inhibits the proliferative and cytotoxic activity of anit-CD3 activated
T-cells
Lin HS, Hu CY, Chan HY, et al. 2007. Anti-rheumatic activities of histone
deacetylase (HDAC) inhibitors in vivo in collagen-induced arthritis in
rodents. British Journal of Pharmacology 150(7): 862-872
Larsen L, Tonnesen M, Ronn SG, et al. 2007. Inhibition of histone
deacetylases prevents cytokine-induced toxicity in beta cells. Diabetologia
50(4):779-789
- HDAC inhibition reduced cytokine mediated decrease in insulin secretion
and increase in iNOS levels
- In response to immune mediated elimination of pancreatic beta cells in
type 1 diabetes
- HDAC inhibition prevents cytokin-induced beta cell apoptosis
Brogdon JL, Xu YY, Szabo SJ, et al. 2007. Histone deacetylase activities are
required for innate immune cell control of Th1 but not Th2 effector cell
function. Blood 109(3):1123-1130
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HDAC inhibition alters TLR 4 dependent activation
Inhibited DC controlled Th1 effector by not Th2 effector activation and
migration
Inhibited macrophage, DC mediated and monocyte but not neutrophil
chemotaxis
Carta S, Tassi S, Semino C, et al. The histone deacetylase inhibitor ITF2357
reduces production of pro-inflammatory cytokines in vitro and systemic
inflammation in vivo. Molecular Medicine (11): 1-15
-
reduced LPS stimulated PBMCs production of
o TNFa (50%)
o IL-1B (50%)
o IL-1A (50%)
o IFN-gamma
Blanchard F, Chipoy C. 2005. Histone deacetylase inhibitors: new drugs for
the treatment of inflammatory diseases?. Drug Discovery Today 10(3):197204
- Putative HDACi reduction of cytokines and NO suggests inhibition of NF-kB
Literature Review Part II: Adenovirus Mediated Gene Therapy
Ajuebor MN, Jin YJ, Gremillion GL, et al. 2008. Gamma delta T cells initiate
acute inflammation and injury in adenovirus-infected liver via cytokinechemokine cross talk . Journal of Virology 82(19):9564-9576
-
Classical innate immune cells NK, neutrophis and Kupffer cells have all
been implicated in the development of Ad-mediated liver toxicity
CXCL9-CXCR3 dependent mechanism governing accumulatio of GDTcells in livers of Ad infected mice
o Recruit CD8+
o CXCL9/IFN-gamma feedback loop to drive proinflammatory effects
of GDTcells during Ad infection
Appledorn DM, McBride A, Seregin S, et al. 2008. Complex interactions with
several arms of the complement system dictate innate and humoral
immunity to adenoviral vectors. Gene Therapy 15(24):1606-1617
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Several studies have suggested that recombinant adenoviruses interact
with the complement system within minutes of the infection
Transcriptome response to rAD was both C3 and Factor B dependent
Also identified C3 dependence of Ad-mediated induction of the NF-kB
pathway
Appledorn DM, Patial S, McBride A, et al. 2008. Adenovirus vector-induced
innate inflammatory mediators, MAPK signaling, as well as adaptive
immune responses are dependent upon both TLR2 and TLR9 in vivo.
Journal of Immunology. 181(3):2134-2144
- Ad directly activates ERK 1/2 BUT ERK 1/2 activation is MyD88/TLR2
independent, Kupffer cell-dependent
- TLR 2 and MyD88 required for sustained activation of ERK1/2 however
- NF-kB induction by Ad dependent on My-D88 and independent of TLR2 in
liver
- TLR2 significantly influenced Ad late phase activation of NF-kB
- TLR is needed for adaptive immune response
o Generation of Ad-neutralizing Abs/ anti-transgene abs
- Several induced innate immune responses are dependent on TLR 2 and 9
Benihoud K, Salone B, Esselin S, et al. 2000. The role of IL-6 in the
inflammatory and humoral response to adenoviral vectors. Journal of Gene
Medicine. 2(3):194-203
- IL-6 plays an important part in acute phase innate response
o Differentiation of B cells and activation of TH2 cells
- While IL-6 plays a role in acute phase innate reponse, antibody and
cellular response to Ad are very similar in WT and IL-6 -/- mice (possibly
to compensatory mechanisms)
Bessis N, GarciaCozar FJ, Boissier MC. 2004. Immune responses to gene
therapy vectors: influence on vector function and effector mechanisms.
Human Gene Therapy 14(7):627-643
- Viral vectors induce immune response due to immunogenic epitope
expression inside the organism
- Large inflammatory cytokine and chemokine secretion profile initially
o Not so much with AAV
- DNA vectors also elicit innate immune response because of CpG islest
- Capsid antigens are mostly responsible for specific immunity against Ad
o Virally encoded proteins can also immunogenic
- Article discusses strategies to fight vector-inuduced immunity
Cotter MJ, Muruve DA . 2005. Neutrophil Interaction with Adenovirus Vectors
During the Innate Immune Response Limit Viral Persistence In Vivo.
Inflammation Research 54:S185
Cotter MJ, Muruve DA. 2005. The induction of inflammation by adenovirus
vectors used for gene therapy. Frontiers in BioScience 10:1098-1105
- Review of cellular and molecular mechanisms involved in the adenovirusmediated inflammatory response
Cotter MJ, Zaiss AK, Muruve DA. 2005. Neutrophils interact with adenovirus
vectors via Fc receptors and complement receptor 1. Journal of Virology
79(23):14622-14631
- 25% of recruited neutrophils interacted with Ad (Cy-2 labled Ad, FACs)
- Ad-neutrophil interaction reduced vector transduction efficiency by more
than 50%
- CAR (coxsackie adenovirus receptor) not present in Neutrophils, blocking
of complement receptor 1 (CD35) greatly reduced neutrophil uptake of Ad
- Blocking of Fc receptors also reduced neutrophil uptake
- Combined CR1 and Fc receptor blockaded synergistically inhibited uptake
of Ad to clost to baseline
- Results demonstrate opsonin-dependent Ad interactions with neutrophils
Descamps D, Benihoud K. 2009. Two Key Challenges for Effective
Adenovirus-Mediated Liver Gene Therapy: Innate Immune Responses and
Hepatocyte-Specific Transduction. Current Gene Therapy 9(2):115-127
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overview of Immune responses mediated by Ad and discussion about how
to optimize delivery, specificity, and maximize transgene expression
Fejer G, Drechsel L, Liese J, et al. 2008. Key Role of Splenic Myeloid DCs in
the IFN-alpha beta Response to Adenoviruses In Vivo. PLOS Pathogens
4(11): e1000208
- Early production of IFNa/b=essential component of antiviral host defense
mechanisms
- Ads elicit strong and rapid IFN-a/b production almost exclusively in splenic
mDCs
- IFN a/b response does not require TLRs, cytosolic sensors of RNA (RIG-I,
MDA-5)
o Instead dependent on viral endosome escape
 Signaling via MAPK, SAPK/JNK and IRF-7
- IFNa/b regulates IL-6 response in vivo
Gardner T, Chen QL, Jin YJ, et al. 2009. Characterization of the role of TCR
gamma delta in NK cell accumulation during viral liver inflammation.
Experimental and Molecular Patholgy 86(1):32-35
- NK cell accumulation but not activation for Poly I:C(polyinosinicpolyctidylic acid) treatment (GD Tcell deficient)
- NK cell accumulated AND activated in TCR gamma delta deficient mouse
strain after Ad infection
Haisma HJ, Kamps JAAM, Kamps GK, et al. 2008. Polyinosinic acid enhances
delivery of adenovirus vectors in vivo by preventing sequestration in liver
macrophages. Journal of General Biology 89:1097-1105
-
-
upon Adenovirus administration, AD is preferentially sequestered by the
liver
o results in reduced transgene expression in targeted tissues
Kupffer cells in liver largely contribute to inflammatory response
Poly(1) (polyinosinic acid-receptor A scavenger) assessed for its ability to
inhibit Ad uptake specifically in macrophages
Pretreatment with Poly(1) caused a 10-fold transient increase in Ad titer in
blood
Transgene levels ehanced 5-15 fold
No liver toxicity observed after poly(1) treatment
Hartman ZC, Appledorn DM, Amalfitano A. 2008. Adenovirus vector induced
innate immune responses: Impact upon efficacy and toxicity in gene
therapy and vaccine applications. Virus Research 132(1-2):1-14
-
Overview of known interactome of Ad virus vectors
Hartman ZC, Kiang A, Everett RS, et al. 2007. Adenovirus infection triggers a
rapid, MyD88-regulated transcriptome response critical to acute-phase and
adaptive immune responses in vivo. Journal of Virology 81(4):1796-1812
-
Used MyD88KO mice to confirm gene expression profile results: Ad-
-
induced dysregulation of five functionally related gene clusters are
significantly dependent on the TLR adaptor gene
MyD88 deficienty resulted in significantly diminished, but not abolished,
adaptive acute-phase immune reponse to Ad
Jager L, Hausl MA, Rauschhuber C, et al. 2009. A rapid protocol for
construction and production of high-capacity adenoviral vectors. Nature
Protocols 4(4):547-564
Kiang A, Hartman ZC, Everett RS, et al. 2006. Multiple innate inflammatory
responses induced after systemic adenovirus vector delivery depend on a
functional complement system. Molecular Therapy 14(4): 588-598
-
comparision of acute-phase protein levels in WT and complement KO
mouse
IL-6, IFN-gamma, RANTES, IL-12(p40), IL-5, G-CSF in WT but not KO
Lieber A, He CY, Meuse L, et al. 1998. Inhibition of NF-kappa B activation in
combination with Bcl-2 expression allows for persistence of first-generation
adenovirus vectors in the mouse liver. Journal of Virology 71(11): 9267-9277
Liu Q, Muruve DA. 2003. Molecular basis of the inflammatory response to
adenovirus vectors. Gene Therapy 10(11):935-940
- Molecular basis for inflammatory response
- Viral capsid (transcription-independent) activates a number of signaling
pathways
o P38 mitogen activated protein kinase (MAPK) and extracellular
signalregulate kinase (ERK)
o Ultimately lead to expression of proinflammatory genes
 Cytokines, chemokines, leukocyte adhesion moleules
McCaffrey AP, Fawcett P, Nakai H, et al. 2008. The host response to
adenovirus, helper-dependent adenovirus, and adeno-associated virus in
mouse liver. Molecular Therapy 16(5): 931-941
-
Ad and HD gene expression programs were very similar
o Prominent type I interferon dependent cluster within the first 6
hours
o AAV caused far fewer alterations in gene expression
o Host recognition of capsid or dsDNA (of nonviral origin) elicits a
robust type I IFM response
 Not elicited by AAV-derived vector transduction
Minter RM, Rectenwald JE, Fukuzuka K, et al. 2000. TNF alpha receptor
signaling and IL-10 gene therapy regulate the innate and humoral immune
responses to recombinant adenovirus in the lung. Journal of Immunology
164(1):443-451
- Can IL-10 (suppressive cytokine) reduce inflammation and extend
duration of transgene expression?
- Also determine the role of TNF-alpha and TNF receptor signaling in Ad
clearance and immune responses
- TNFa signaling through p55 and 74 plays important roles in clearance of
Ad vectors and the magnitude of the humoral response
Mok H, Park JW, Park TG. 2007. Microencapsulation of PEGylated
adenovirus within PLGA microspheres for enhanced stability and gene
transfection efficiency. Pharmaceutical Research 24(12): 2263-2269
Moro MR, Bonville CA, Suryadevara M, et al. 2009. Clinical Features,
Adenovirus Types, and Local Production of Inflammatory Mediators in
Adenovirus Infections. Pediatric Infections Disease Journal 28(5) 376-380
Muruve DA, Petrilli V, Zaiss AK, et al. 2008. The inflammasome recognizes
cytosolic microbial and host DNA and triggers an innate immune response.
Nature 452(7183): 103-U11
Muruve DA. 2004. The innate immune response to adenovirus vectors.
Human Gene Therapy 15(12):1157-1166
Nakashima K, Sakurai F, Kawabata K, et al. 2008. Efficient gene delivery in
human and rodent mast cells using adenovirus vectors. Journal of Controlled
Release. 129(3): 215-222
Nazir SA, Metcalf JP. 2005. Innate immune response to adenovirus. Journal
of Investigative Medicine 53(6):292-304
Nociari M, Ocheretina O, Murphy M, et al. 2009. Adenovirus Induction of IRF3
Occurs through a Binary Trigger Targeting Jun N-Terminal Kinase and
TBK1 Kinase Cascades and Type I Interferon Autocrine Signaling. Journal
of Virology 83(9):4081-4091
Nociari M, Ocheretina O, Schoggins JW, et al. 2007. Sensing infection by
adenovirus: Toll-like receptor-independent viral DNA recognition signals
activation of the interferon regulatory factor 3 master regulator. Journal of
Virology 81(8): 4145-4157
Perreau M, Kremer EJ. 2006. The conundrum between immunological
memory to adenovirus and their use as vectors in clinical gene therapy.
Molecular Biotechnology 34(2):247-256
Ritter T, Lehmann M, Volk HD. Improvements in gene therapy - Averting the
immune response to adenoviral vectors. 2002. BioDrugs 16(1):3-10
Sakurai H, Igarashi K, Tashiro K, et al. 2008. Analysis of gene expression
profile involved in the innate immune response by adenovirus vector.
Journal of Gene Medicine 10(4):468
 IL6 and IL12
 CXCL10 and CCL4
 Interferon Inducible genes
 TLR 2 and TLR 3
 Differential expression in in vivo repsponse in spleen and liver
Sakurai H, Kawabata K, Sakurai F, et al. 2008. Innate immune response
induced by gene delivery vectors. International Jouranl of Pharmaceutics
354(1-2):9-15
Sakurai H, Tashiro K, Kawabata K, et al. 2008. Adenoviral expression of
suppressor of cytokine signaling-1 reduces adenovirus vector-induced
innate immune responses. Journal of Immunology 180(7):4931-4938
Schaack J. 2005. Induction and inhibition of innate inflammatory responses
by adenovirus early region proteins. Viral Immunology 18(1):79-88
Segura MM, Alba R, Bosch A, et al. 2008. Advances in helper-dependent
adenoviral vector research. Current Gene Therapy. 8(4):222-235
Shayakhmetov DM, Li ZY, Ni SH, et al. 2005. Interference with the IL-1-
signaling pathway improves the toxicity profile of systemically applied
adenovirus vectors. Journal of Immunology 174(11):7310-7319
Yanagi K, Nagayama Y, Nakao K, et al.2003. Immuno-gene therapy with
adenoviruses expressing fms-like tyrosine kinase 3 ligand and CD40
ligand for mouse hepatoma cells in vivo. International Journal of Oncology
22(2): 345-351
Zaiss AK, Cotter MJ, White LR, et al. 2008. Complement is an essential
component of the immune response to adeno-associated virus vectors.
Journal of Virology 82(6):2727-2740
Zaiss AK, Liu Q, Bowen GP, et al. 2002. Differential activation of innate
immune responses by adenovirus and adeno-associated virus vectors.
Journal of Virology 76(9): 4580-4590
Zhang Y, Chirmule N, Gao GP, et al. 2001. Acute cytokine response to
systemic adenoviral vectors in mice is mediated by dendritic cells and
macrophages. Molecular Therapy 3(5): 697-707
Zhu JA, Huang XP, Yang YP. 2008. A critical role for type I IFN-dependent
NK cell activation in innate immune elimination of adenoviral vectors in
vivo. Molecular Therapy 16(7): 1300-1307
Zhu JG, Huang XP, Yang YP. 2007. Type IIFN signaling on both B and CD4
T cells is required for protective antibody response to adenovirus. Journal of
Immunology 178(6): 3505-3510
Zhu JG, Huang XP, Yang YP. Innate immune response to adenoviral vectors
is mediated by both Toll-like receptor-dependent and -independent
pathways. Journal of Virology 81(7): 3170-3180
(Further literature cited in review article Innate immune response induced by
gene delivery vectors)
Basner-Tschakarjan et al., 2006. Adenovirus efficiently transduces plasmacytoid
dendritic cells resulting in TLR9-dependent maturation and IFN-alpha production,
J. Gene. Med. 8 (2006), pp. 1300–1306.
Borgland et al., 2000. Adenovirus vector-induced expression of the C–X–C
chemokine IP-10 is mediated through capsid-dependent activation of NFkappaB, J. Virol. 74 (2000), pp. 3941–3947.
G.P. Bowen, S.L. Borgland, M. Lam, T.A. Libermann, N.C. Wong and D.A.
Muruve. Adenovirus vector-induced inflammation: capsid-dependent induction of
the C–C chemokine RANTES requires NF-kappaB, Hum. Gene. Ther. 13 (2002),
pp. 367–379.
Colonna et al., 2004 M. Plasmacytoid dendritic cells in immunity, Nat. Immunol. 5
(2004), pp. 1219–1226.
Hartman et al., 2007. Adenovirus infection triggers a rapid, MyD88 regulated,
transcriptome response critical to acute phase and adaptive immune responses
in vivo, J. Virol. 81 (2007), pp. 1796–1812.
Kawai and Akira, 2006. Innate immune recognition of viral infection, Nat.
Immunol. 7 (2006), pp. 131–137.
Schnell et al., 2001. Activation of innate immunity in nonhuman primates
following intraportal administration of adenoviral vectors, Mol. Ther. 3 (2001), pp.
708–722.
Literature Review Part II (B):
Interferon Responsive Genes (Type I), NF-kB genes, and MAPK cytokines
MacDonald MR. et al. 2007. The Zinc Finger Antiviral Protein Acts Synergistically
with an Interferon-Induced Factor for Maximal Activity against Alphaviruses.
Journal of Virology 81(24): 13509-13518.
 Overexpression of the zinc finger antiviral protein (ZAP) imparts a cellular
antiviral state
Wei L. et al. 2006. NF{kappa}B Negatively Regulates Interferon-induced Gene
Expression and Anti-influenza Activity. J. Biol. Chem 28(17):11678-11684.
 IFN treatment resulted in the recruitment of STAT1 and STAT2 to
promoters. However, in NF{kappa}B knock-out cells IFN induced STAT
binding as well as the binding of the IFN regulatory factor-1 (IRF1) to the
IFN-stimulated gene (ISG) promoters. IRF1 binding closely correlated
with enhanced gene induction.