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Alzheimer's disease susceptibility gene products related to Herpes Simplex (see AD genes for genetic association references) These interactions formed the basis of the following papers, and are updated.Interactions between the products of the Herpes simplex genome and Alzheimer's disease susceptibility genes: relevance to pathological-signalling cascades.Neurochem Int. 2008 ;52(6):920-34 APP, APOE, complement receptor 1, clusterin and PICALM and their involvement in the herpes simplex life cycle Neuroscience Letters,483, 96-100. 2010. Alzheimer’s disease plaques and tangles: Cemeteries of a Pyrrhic victory of the immune defence network against herpes simplex infection at the expense of complement and inflammation–mediated neuronal destruction.Neurochem Int, in press 2010 Alzheimer's disease: a pathogenetic autoimmune disorder caused by herpes simplex in a gene-dependent manner.Int.J.Alz.Dis, 2010 See also the Alzforum live discussion on Herpes simplex and Alzheimer's disease The fox and the rabbits, environmental variables and population genetics.1: Replication problems in association studies and the untapped power of GWAS. 2: Vitamin A deficiency, herpes simplex reactivation and other causes of Alzheimer’s disease ISRN neurology, 2011 Human transcription factors binding to the HSV-1 genome control the transcription of many genes relevant to Alzheimer's disease. Herpes simplex infection in mice causes decreased brain volume, entorhinal and hippocampal neuronal loss and memory deficits Armien et al, 2010 PUBMED links Herpes+ Alzheimer's |
Database of Herpes simplex (HSV-1) host-viral interactions ............KEGG pathway analysis of the HSV-1 life cycle
KEGG pathway analysis of Alzheimer's disease susceptibility gene candidates
KEGG pathway analyis of the herpes simplex life cycle
Direct and indirect interactions between Alzheimer's susceptibility gene products and HSV-1 |
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Major players |
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| APOE Apolipoprotein E | Glycoprotein B (UL27) binds to proteoliposomes containing APOE or APOA1 Huemer et al, 1988 APOE4 acts in synergy with HSV-1 infection to promote risk in Alzheimer's disease Lin et al, 1996 APOE4 favours cerebral HSV-1 infection in mice Burgos et al, 2003 |
| CR1 Complement receptor 1 | HSV-1 and the influenza virus bind to CR1 on human erythrocytes Powers et al, 1995 Complement cascade The Herpes simplex viral glycoprotein C acts as a CR1 mimic and, like CR1, binds to complement C3 components, blocking complement pathways and preventing the formation of the membrane attack complex Huemer et al, 1993 |
| CLU Clusterin: Apolipoprotein J | See below Complement cascade Clusterin inhibits formation of the membrane attack complex by binding to C7, C8, and C9 Tschopp et al, 1993 HSV-1 infection increase clusterin expression in BHK cells Hope et al. 1982 |
| PICALM phosphatidylinositol binding clathrin assembly protein Aliases: CALM, CLTH, LAP | The Mannose-6-phosphate receptor (M6PR) is used by Herpes simplex in certain cells Brunetti et al 1995 . This receptor is also involved in the routing of the virus to endosomes Brunetti et al. 1998 and the viral glycoprotein D blocks the entry of lysosomal enzymes to the endosomal compartment by binding to this receptor; one of several ways by which the virus blocks apoptosis {Zhou & Roizman 2002 . The mannose-6-phosphate receptor binds to clusterin Lemansky et al, 1999 and its traffic through the endosomal compartments is controlled by PICALM, whose overexpression reduces M6PR localisation in endosomes, suggesting blockade of its transport from the plasma membrane or the trans-golgi network Tebar et al, 1999 . The herpes simplex virus also uses exportin (Crm1 XPO1 ) dependent pathways for nuclear egress Williams et al, 2008 PICALM and other endocytic-regulatory proteins bind to Crm1 Vecchi et al, 2001 |
| BIN1, CD33, EPHA1, MS4A cluster | Alzheimer’s disease: APP, gamma secretase, APOE, CLU, CR1, PICALM, ABCA7, BIN1, CD2AP, CD33, EPHA1 and MS4A2, and their relationships with herpes simplex , C.Pneumoniae, other suspect pathogens and the immune system: Int.J.Alz.Dis, 2011 |
Lesser players |
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| A2M alpha-2-macroglobulin | Binds to HSV1 Alonso et al, 2001 |
| APOA1 | Glycoprotein B (UL27) binds to proteoliposomes containing APOA1 Huemer et al, 1988 .APOA1 inhibits HSV-1 induced cell fusion Srinivas et al, 1991 |
| APP Amyloid beta (A4) precursor protein | Involved in the fast anterograde transport of Herpes simplex (in squid axons) Salpute-Krishnan et al, 2003. Herpes simplex DNA is found in amyloid plaques in AD Wozniak et al, 2009 HSV-1 infection increases beta-amyloid deposition in neuronal/glial cells Wozbiak et al, 2007. The APP binding protein APPBP2 also binds to HSV-1 protein US11 and is involved in its intracellular transport Benboidjema et al, 2003 Fibrillar beta-amyloid promotes viral entry Wojtowicz et al, 2002 Acyclovir or Abeta42 peptides attenuate HSV-1-induced miRNA-146a levels in human primary brain cells Lukiw et al, 2010. Beta amyloid, IL1B or oxidative stress also increase mir146a expression in cultured neural cells, and mir146a expression is increased in Alzheimer's the disease brain Lukiw et al, 2008. |
| CDC2 cell division cycle 2 protein, p34 protein kinase; cyclin-dependent kinase 1 (CDK1) | Components of the herpes virus (UL13 and ICP22) activate the host cyclin dependendent kinase CDC2 which in turn phosphorylates herpes simplex proteins including ICP0 and potentially 26 other HSV proteins that contain cdc2 concensus phosphorylation sites Advani et al, 2000 |
| CFH Complement factor H | Glycoprotein C of HSV-1 inhibits CFH binding to complement C3B Huemer et al, 199 |
| DNM2 Dynamin 2 | Mediates internalisation of the Herpes viral VP22 protein in CHO cells Nishi and Saigo, 2007 |
| EIF2AK2 PKR eukaryotic translation initiation factor 2-alpha kinase 2 | Like many viruses, HSV-1 activates PKR, but has evolved various defensive strategies to combat its effects. One viral gene product (ICP34.5) is highly homologous to the host GADD34 (PPP1R15A) and dephosphorylates the PKR target eif2alpha,Cassady et al, 1998 while another, US11, prevents PKR activation by inhibiting the PKR activator PACT (PRKRA) Peters et al, 2001. US11 also binds to PKR Cassady and Gross, 2002 |
| FCER1G Fc fragment of IgE, high affinity I, receptor for; gamma polypeptide | Two herpes simplex proteins, glycoproteins E and L (US8, UL1) form a decoy Fc receptor. This is expressed on the surface of virions and infected cells and binds to host immunoglobulin G. IgG is released from this receptor by the acidic conditions present in lysosomes and this receptor may thus promote the degradation of antiviral antibodies bound to IgG. It has also been suggested that the entrapment of antiviral antigens by this viral Fc receptor may divert their binding to host Fc receptors Sprague et al, 2006 (eg FCER1G). |
| GAPDH glyceraldehyde-3-phosphate dehydrogenase | Incorporated into the HSV-1 Virion Loret et al, 2008 |
(Gamma-secretase components) |
Gamma-secretase cleaves nectin 1-alpha (PVRL1) Kim et al, 2002 and Syndecans 1and 2 Hemming et al, 2008, all entry receptors for the Herpes Virus Krummenacher et al, 1998; Cheshenko et al, 2007 , HSV-1 infection increases BACE1 and NCSTN expression in cells Wozniak et al, 2007 |
| HLA-A2
major histocompatibility complex, class I, A |
One of many MHC's involved in Herpes viral recognition Chan et al, 1989 |
| HSPG2 heparan sulfate proteoglycan 2 (perlecan) | Glycoproteins B and C of Herpes simplex bind to Heparan sulfate proteoglycans Bender et al, 2005 |
| IDE. Insulin degrading enzyme | IDE is a Varicella zoster receptor that also binds to HSV-1 glycoprotein E Li and Cohen, 2006 |
| IL6 Interleukin 6 | Binds to IL6 response elements in the LAT promoter and ICP0 genes of HSV-1Kriesel et al, 1997 : Transgenic CNS expression of IL6 protects against acute herpes simplex virus type-1 infection.Carr and Campbell, 1999 |
| LCK Lymphocyte tyrosine kinase | Viral proteins VP11/VP12 phosphorylate LCK Wagner and Smiley, 2009 |
| LMNA lamin A/C | Binds to viral proteins UL31 and UL34 Reynolds et al, 2004. ICP8 binds to LMNA and PARP1 Taylor and Knipe 2004 |
| PARP1 poly (ADP-ribose) polymerase family, member 1 | HSV-1 protein ICP8 binds to LMNA and PARP1 Taylor and Knipe 2004 |
| POU2F1 Pou domain Class 2, transcription factor1 | Herpes viral protein VP16 associates with two host proteins, host cell factor-1(HCFC1) and POU2F1 forming a multiprotein enhancer complex responsible for the transcription of viral immediate early genes Wysocka and Herr, 2003 |
| PVRL2 poliovirus receptor-related 2 (herpesvirus entry mediator B) | HSV-1 glycoprotein D binds to PVRL2, a viral entry receptor Warner et al, 1998 |
TAP2 transporter 2, ATP-binding cassette, sub-family B (MDR/TAP) antigen peptide transporter 2 |
Inhibited by the viral protein ICP47 (HSV1 and 2) Galocha et al, 1997 |
| TFCP2
Transcription factor CP2 (CP2; LSF; LBP-1C; TFCP2C) |
Binds to the origin of replication site of HSV-1 Dabrowski et al, 1994 |
| TGFB1
transforming growth factor, beta 1 |
The HSV-1 latency-associated transcript encodes a microrna for TGFB1 with anti-apoptotic functions Gupta et al, 2006. |
| TRAF2 TNF receptor-associated factor 2 | Binds to many TNF receptors including the Herpes Viral entry mediator TNFRSF14 |
| TP53 Tumor protein P53 | HSV-1 protein ICP0 binds to and ubiquitinates TP53 Boutell and Everett, 2003 |
Alzheimer's susceptibility genes that modify HSV-1 infection |
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| CCL2 chemokine (C-C motif) ligand 2 , MCP-1 | The U83 gene of HHV-6 encodes a CCL2 mimic acting via CCR2 Luttichau et al, 2003. CCL2 enhances HSV-1 infectivity in mice Nakijama et al, 2001. |
| CCR2 chemokine (C-C motif) receptor 2 (receptor for CCL2) | See above |
| CST3
cystatin C (amyloid angiopathy and cerebral hemorrhage) (Cathepsin S inhibitor) |
Blocks HSV-1 replication Blorck et al, 1990 |
| HSV infection results in a large and rapid reduction in cellular glutathione levels in host cells. Glutathione inhibits Herpes viral replication in vitro, while S-acetylglutathione, a prodrug that increases cellular glutathione levels is effective following systemic injection in mice Palamara et al, 1995. Vogel et al, 2005 | |
| ICAM1 intercellular adhesion molecule 1 (CD54), human rhinovirus receptor | HSV-1 infectivity is increased in ICAM-1 knockout mice Noisakran et al, 2005 |
| IL1A: Interleukin 1alpha | Protects mice against HSV-1 infection. Berkowitz and Becker, 1992 |
| ILIRN interleukin 1 receptor antagonist | IL1RN transgenic mice are resistatnt to occular HSV infectionBiswas et al, 2004 |
| IL18 interleukin 18 (interferon-gamma-inducing factor) | Protects mice against HSV-1 infection Fujioka et al, 1999 |
| MAPK8IP1
mitogen-activated protein kinase 8 interacting protein 1 |
HSV-1 infection activates c-jun N-terminal kinase (JNK), an effect that enhances viral replication. MAPK8IP1 , a JNK inhibitor reduces viral yield McLean and Bachenheimer, 1999 |
| NOS1 nitric oxide synthase 1 (neuronal) NOS2 nitric oxide synthase 2, inducible; NOS3 nitric oxide synthase 3 (endothelial cell, eNOS) |
Activation of neuronal NOS inhibits HSV-1 replication in neurones Komatsu et al, 1996. Nitric oxide inhibits viral replication Torre et al, 2002, possibly by S-nitrosylation of viral proteins Colasanti et al, 1999 |
| PIK3R1
phosphoinositide-3-kinase, regulatory subunit, polypeptide 1 (p85 alpha) |
HSV-1 infection produces a transient phosphorylation of ser473 of the AKT1 kinase, an effect that is PI3K dependendent.Activation of this survival pathway may act to prevent apoptosis. The particular isoform of PI3K was not specified.Benetti and Roizmann, 2006 : HSV-1 toxicity is increased in PIK3R1 knockout fibroblasts Prejean et al, 2001 |
| PRNP
prion protein |
Herpes simplex infectivity is reduced in PRNP knockout mice Thackray and Bujdoso, 2006 |
| PTGS2 prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase) COX-2 | Non-steroidal anti-inflammatory drugs that inhibit cyclooxygenase also attenuate herpes viral reactivation.Herpes infection increases the expression and activity of PTGS2 Reynolds and Enquist, 2006 |
Genes whose expression is modified by infection |
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| BACE1 beta-site APP-cleaving enzyme 1 | HSV-1 infection increases Bace1 and NCSTN expression in cells Wozniak et al, 2007 |
| CHAT
choline acetyltransferase |
HSV1 infection reduces choline acetyltransferase (CHAT) and acetylcholinesterase ACHE acivity in PC12 cell Rubenstein and Price, 1984 |
| CRP: C-reactive protein | CRP levels are a general reflection of pathogen burden (HSV-1 and others) Zhu et al, 2000 |
| CTSD : cathepsin D (lysosomal aspartyl protease) | Upregulated by Virion binding to Vero cells McLeod and Minsen, 2010 |
| FAS Fas (TNF receptor superfamily, member 6) | Upregulated by Virion binding to Vero cells McLeod and Minsen, 2010 |
| LDLR Low density lipoprotein receptor | HSV-1 infection increases LDLR expression and transcription in arterial smooth muscle cells Hsu et al, 1995 |
| OLR1
oxidised low density lipoprotein (lectin-like) receptor 1 (LOX1; SCARE1) |
HSV-1 increases OLR1 expression in endothelial cells Chirathaworn et al, 2004 |
| PLAT (tPA) plasminogen activator, tissue | Pai-1 and tPA levels are decreased in endothelial cells by HSV-1 infection Bok et al, 1993 |
| SERPINE1 serpin peptidase inhibitor, clade E (nexin, plasminogen activator inhibitor type 1)PAI-1 | Pai-1 and TPA levels are decreased in endothelial cells by HSV-1 infection Bok et al, 1993 |
TLR4 Toll-like receptor 4 |
Upregulated by HSV-1 infection (encephalitis) in mice Bottcher et al, 2003 |
| VEGFA Vascular endothelial growth factor | Herpes simplex viral DNA promotes angiogenesis by increasing the expression of VEGF, an effect attributed to a direct effect of unmethylated cPG motifs in the viral DNA Zheng et al, 2002. |
Related to viral transport |
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| DNM2 Dynamin 2 | Mediates internalisation of the Herpes viral VP22 protein in CHO cells Nishi and Saigo, 2007 |
| DNMBP Dynamin Binding protein | Not specifically studied in relation to HSV-1, but related to DNM2 |
| MYH13 myosin, heavy chain 13, skeletal muscle | Herpes viral capsids use myosins for active transport within the nucleus Forest et al, 2005 Feierbach et al, 2005: These particular myosins has not been specifically examined. |
| MYH8 Myosin heavy polypeptide 8 | see above |
| KIF18B kinesin family member 18B | Kinesins play an important role in HSV-1 transport along microtubules Lee et al, 2006. The role of these particular kinesins has not been examined. KNS2 does however bind to APP Kamal et al, 2001which is involved in viral transport Salpute-Krishnan et al, 2003 |
| KNS2 kinesin 2 (KLC1) | |
| MAPT
microtubule-associated protein tau |
A viral tegument protein, VP22, results in the hyperacetylation of microtubules Elliot and O'Hare,1998, a property shared by unphosphorylated tau (MAPT) Cho and Johnson, 2004and both tau and VP22 are able to stabilise microtubules via this mechanism. (MAPT is involved in the traffic of other viruses (JHM coronavirus) but its role in herpes traffic has not been specifically examined Kallicharran and Dales, 1995. |
| TRAK2 trafficking protein, kinesin binding 2 | Not specifically studied but related to kinesins |
Miscellaneous Genes |
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| BLMH
Bleomycin hydrolase |
Bleomycin inhibits Herpes and other viral replication Norskov-Lauritsen and Ebbesen 1993 |
| CTNNA3 catenin (cadherin-associated protein), alpha 3 (VR22) | The Herpes simplex virus enters host cells via a number of different receptors including the herpes virus entry mediator (HVEM: Gene symbol TNFRSF14), and members of the nectin receptor family (PVRL1-4). Nectins are adhesion molecules connected to the actin cystoskeleton and recruited to cadherin-based adherens cell-cell junctions via afadin (MLLT4) Takahashi et al, 1999.The cadherin and nectin adhesion systems are interconnected via alpha-catenin (CTNNA3) Tachibana et al, 2000which binds to afadin Pokutta et al, 2002. |
| MEF2A MADS box transcription enhancer factor 2, polypeptide A (myocyte enhancer factor 2A) | The ICP0 protein of HSV1 interacts with histone deacetylases (HDAC4,5 and 9) via an amino terminal domain responsible for suppressing the activity of myocyte enhance factor MEF2A by nuclear sequestration. ICP0 overcomes the HDAC mediated suppression of MEF2A Lomonte et al, 2004 |
| UBQLN1 Ubiquilin 1 | The HSV protein ICP0 contains two E3 ubiquitin ligase domains, one of which binds to the host ubiquitin conjugating enzyme CDC34 Haggland et al, 2002and another that binds to host UbcH5a (UBE2D1)- and UbcH6 (UBE2E1) E2-conjugating enzymes Gu and Roizman, 2003. Both these E2 conjugating enzymes are known to complex with the ubiquitin ligase e6ap (UBE3A) Nuber and Scheffner, 1999,which in turn binds to both ubiquilins (UBQLN1, 2) Kleijnen et al, 2000. |
Mitochondrial gene deletions in Alzheimer's disease |
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A truncated form of the herpes simplex protein, UL12 (UL12.5), localises to mitochondria and deletes host mitochondrial DNA Saffran et al, 2007. |
Immune-related genes Immune system |
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Although not specifically related to Herpes simplex, (with the exception of C4, EIF2AK2, FCER1G, and TAP2) the immune system defends against pathogen attack. Complement C4A and C4B deficiency increases intraoral Herpes viral infection Seppanen et al, 2001. HSV-1 infection downregulates CFH expression in human brain cells Hill et al, 2009 . HSV-1 glycoprotein C inhibits the binding of CFH to complement C3 Huemer et al, 1993 Biocarta pathway for stress activated kinases including EIF2AK2 Wikipedia |
CHEMOKINES and CYTOKINES:
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Chemokines and cytokines are generally involved in inflammatory responses to pathogen attack IL6 interacts directly with the viral genome (see above) |
Cholesterol and lipoprotein related genes |
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CHOLESTEROL ENZYMES;
LIPID RAFTS CAV1 Caveolin 1 caveolae protein RFTN1 Raftlin lipid raft linker 1: CHOLESTEROL TRANSPORT;
LIPOPROTEINS Lipoprotein receptors
Transcription factors regulating cholesterol/lipoprotein physiology; |
HSV-1 entry into Vero cells is lipid raft dependent and is blocked by the cholesterol synthesis inhibitor, nystatin Bender et al, 2003 HSV-1 can be found in all classes of lipoprotein in the blood (LDL, VLDL, HDL) although only APOA1 and APOE have been specifically tested as viral binding agents Huemer et al, 1988
HSV-1 infection of arterial smooth muscle cells increases cholesteryl ester accumulation Hajjar et al, 1989 and increases expression of the Low density lipoprotein recaptor LDLR and increases LDL binding and uptake Hsu et al, 1995 POU2F1 binds to the HSV-1 genome Douville et al, 1995 Other human transcription factors binding to the HSV-1 genome control the transcription of many genes relevant to Alzheimer's disease
Cholesterol related gene pathways in alzheimer's disease Carter 2007 . Papassotiropoulos et al, 2005 |
Alzheimer's disease susceptibility genes affecting HSV-1 infection in Man |
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| APOE4 | APOE4 favours cerebral HSV-1 penetration in mice Burgos et al, 2003 Human HSV-1/APOE4 reviewed in Itzhaki, 2004 and Kuhlman et al, 2010 |
| HLA-DRB1 major histocompatibility complex, class II, DR beta 1 | Associated with Herpes related meningitis Kallio-Laine et al, 2009 |
| IL10 Interleukin 10 | Modifies viral infection Hurme et al, 2003 |
Other relevant effects of Herpes Simplex infection |
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| HSV-1 increases the expression of microRNA mir146a (predicted targets) in cultured neural cells Hill et al, 2009: Beta amyloid, IL1B or oxidative stress also increase mir146a expression in cultured neural cells, and mir146a expression is increased in Alzheimer's the disease brain Lukiw et al, 2008. | |
| HSV-1 increases tau phosphorylation via GSK3B and protein kinase A in neuroblastoma cells Wozniak et al, 2009, and induces tau hyperphophorylation in cultured neurones Zambrano et al, 2008. Tau phosphorylation is a key pathological feature in Alzheimer's disease Hanger et al, 2009 | |
| HSV-1 infection increases beta-amyloid deposition in vero cells and in the brains of infected mice: BACE-1 and nicastrin expression is also increased by cellular viral infection Wozniak et al, 2007 | |
| HSV-1 infection in mice results in entorhinal cortex and hippocampal neuronal loss and memory deficits (as in Alzheimer's disease entorhinal / Hippocampal ) Armien et al, 2010 cf APP transgenics Kockjohn and Roher 2009 See also Alzheimer's disease progression video from the Thompson lab | |
| Beta- amyloid and other fibrillar peptides favour viral entry Wojtowicz et al, 2002 | |
| HSV-1 DNA is found in amyloid plaques in Alzheimer's disease Wozniak et al, 2009. | |
| Pathogens (including HSV-1 Conrady et al, 2010) and beta-amyloid (Salminen at al, 2009) activate pattern recognition receptors involved in pathogen defense suggesting that beta-amyloid may have a sequence signature close to that of certain pathogens. | |