From: Kofi on
After all this time, I tested for a few viruses and my titers came back
positive for Varicella Zoster (the virus behind chicken pox and the
shingles), HHV6 and cytomegalovirus (CMV, which can cause chronic
fatigue and colitis). Many if not most people have these viruses, often
from birth. It's likely my mercury exposure reawakened them.

I've been taking butyrate in an attempt to deal with an autoimmune
intestinal problem for reasons I've outlined in many posts, but recently
my progress has hit a plateau. I think the viral titers help to explain
this and I thought I'd share what I'd found. It appears butyrate can
wake up certain latent herpes viruses in the trigeminal nerve [PMID
17881451] (interesting connection to my TMJ/bruxism, by the way). Since
butyrate is widely used for colitis and being considered for even
greater application, this may be an important contraindication.

So, the question is, does butyrate supplementation wake up latent CMV
infections in the gut. Does the body downregulate butyrate
uptake/histone acetylation as a strategy to prevent viral replication?
If so, this might explain the loss of carnitine uptake via Atb0+/OCTN2
seen in colitis [PMID 17065219]. Lose carnitine and you lose butyrate
uptake and histone regulation. I have no firm link in the literature to
support this, but a CMV infection would provide the body with ample
incentive to attempt exactly this kind of adaptive strategy.

I am aware of links in heart failure that explain why viral infection
can lead to epigenetic dysregulation and metal accumulation in heart
tissue (and I posted on this a few weeks back), but I haven't found much
in pubmed to suggest any link between CMV and butyrate metabolism in the
gut.

There's evidence mercury exposure can reawaken these viruses and
aggravate the infection [PMID 8931761, 8686573, 7526487], but little
explaining a direct connection. There's also some thin evidence
indicating the body might downregulate insulin/IGF-I/gh signaling to
block viral replication as well. I'm aware that metallothionein is
under HDAC control so I can see how an HHV infection might impair detox
leading to metals accumulation but I suspect there's a more direct link.
I find it hard to believe that the last papers on this topic in pubmed
are a decade old.

____________ Notes _____________


CMV is frequently reactivated in ulcerative colitis patients but often
resolves on its own without antivirals [PMID 17156136]

CMV is more common in steroid-refractory ulcerative colitis and
antiviral therapy has a high success rate at achieving remission [PMID
17026558]

patients with ulcerative colitis have more detectable CMV DNA in their
blood and intestinal tissue than controls; Crohn�s patients only had
greater CMV DNA in their intestinal tissue [PMID 16954807]

Anti-TNFalpha agents aggravate CMV colitis infections [PMID 18473420,
18614396, 18452205]


Arch Pharm Res. 2005 Nov;28(11):1293-301.

Antiherpetic activities of flavonoids against herpes simplex virus type
1 (HSV-1) and type 2 (HSV-2) in vitro.
Lyu SY, Rhim JY, Park WB.
Immune Modulation Research Group, The School of Pharmacy, University of
Nottingham, University Park, Nottingham, NG7 2RD, UK.

Flavonoids, a group of low molecular weight phenylbenzopyrones, have
various pharmacological properties including antioxidant, anticancer,
bactericidal, and anti-inflammatory. We carried out anti-herpetic assays
on 18 flavonoids in five classes and a virus-induced cytopathic effect
(CPE) inhibitory assay, plaque reduction assay, and yield reduction
assay were performed. When flavonoids were applied at various
concentrations to Vero cells infected by HSV-1 and 2, most of the
flavonoids showed inhibitory effects on virus-induced CPE. Among the
flavonoids, EC, ECG (flavanols), genistein (isoflavone), naringenin
(flavanone), and quercetin (flavonol) showed a high level of CPE
inhibitory activity. The antiviral activity of flavonoids were also
examined by a plaque reduction assay. EC, ECG, galangin, and kaempferol
showed a strong antiviral activity, and catechin, EGC, EGCG, naringenin,
chrysin, baicalin, fisetin, myricetin, quercetin, and genistein showed
moderate inhibitory effects against HSV-1. In these experiments,
flavanols and flavonols appeared to be more active than flavones.
Furthermore, treatment of Vero cells with ECG and galangin (which
previously showed strong antiviral activities) before virus adsorption
led to a slight enhancement of inhibition as determined by a yield
reduction assay, indicating that an intracellular effect may also be
involved.

Publication Types:
* Research Support, Non-U.S. Gov't

PMID: 16350858


J Virol. 2008 Aug 27;

Establishment of Murine Cytomegalovirus Latency in vivo is Associated
with Changes in Histone Modifications and Recruitment of Transcriptional
Repressors to the Major Immediate Early Promoter.

Liu XF, Yan S, Abecassis M, Hummel M.
Transplant Division, Department of Surgery, Department of Microbiology
and Immunology, Robert H. Lurie Cancer Center, Northwestern University
Feinberg School of Medicine, Chicago, IL.

Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus with the
ability to establish a lifelong latent infection. The mechanism by which
this occurs has not been well understood. Regulation of ie gene
expression is thought to be a critical control point in transcriptional
control of the switch between latency and reactivation. Here, we present
evidence that supports previous studies showing that the majority of
genomes are quiescent with respect to ie gene expression. To study the
possible role of epigenetic factors that may be involved in repression
of ie gene expression in latency, we have analyzed changes in the
patterns of modifications of histones bound to the MIEP in the kidneys
of acutely and latently infected mice. Our studies show that, like HSV,
MCMV genomes become relatively enriched in histones in latent infection.
There are dramatic changes in modifications of histones associated with
the MIEP when latency is established: H3 and H4 become hypoacetylated
and H3 is hypomethylated at lysine 4, while H3 lysine 9 is
hypermethylated in latently infected mice. These changes are accompanied
by a relative loss of RNA polymerase and gain of HP-1gamma and YY1 bound
to the MIEP. Our studies suggest that, in the majority of cells, CMV
establishes a true latent infection, defined as the lack of expression
of genes associated with productive infection, and that this occurs
through changes in histone modifications and recruitment of
transcriptional silencing factors to the MIEP.

PMID: 18753203

Virol. 2008 Jul 23;

Dynamic histone H3 acetylation and methylation at human cytomegalovirus
promoters during replication in fibroblasts.
Cuevas-Bennett C, Shenk T.
Department of Molecular Biology, Princeton University, Princeton, New
Jersey 08544-1014.

Human cytomegalovirus DNA is packaged in virions without histones, but
associates with histones upon reaching the nucleus of an infected cell.
Since transcription is modulated by the interplay of histone
modifications, we employed chromatin immunoprecipitation to detect
acetylation and methylation of histone H3 at viral promoters at
different times during the viral replication cycle. Histone H3 at
immediate-early promoters is acetylated at the start of infection while
it is initially methylated at early and late promoters. Acetylation at
immediate-early promoters is dynamic, with a high level of activating
modifications at 3 and 6 h post-infection (hpi) followed by a marked
reduction at 12 hpi. All viral promoters, as well as non-promoter
regions, are modified with activating acetylations at 24-72 hpi. The
transient reduction in histone H3 acetylation at the major
immediate-early promoter depends on the cis-repressive sequence to which
the UL122-coded IE2 protein binds. A mutant virus lacking this element
exhibited decreased IE2 binding at the MIEP and failed to show reduced
acetylation of histone H3 residing at this promoter at 12 hpi. Our
results demonstrate that cytomegalovirus chromatin undergoes dynamic,
promoter-specific histone modifications early in the infectious cycle,
after which the entire chromosome becomes highly acetylated.

PMID: 18653451

Immunol. 2007 Dec 15;179(12):8235-42.

Molecular regulation of MHC class I chain-related protein A expression
after HDAC-inhibitor treatment of Jurkat T cells.

Andresen L, Jensen H, Pedersen MT, Hansen KA, Skov S.
Department of Immunology, Institute of International Health, Immunology
and Microbiology, University of Copenhagen, Copenhagen, Denmark.

In this study, we characterize the molecular signal pathways that lead
to MHC class I chain-related protein A (MICA) expression after histone
deacetylase (HDAC)-inhibitor (HDAC-i) treatment of Jurkat T cells.
Chelating calcium with BAPTA-AM or EGTA potently inhibited HDAC- and
CMV-mediated MICA/B expression. It was further observed that endoplasmic
reticulum calcium stores were depleted after HDAC treatment. NF-kappaB
activity can be induced by HDAC treatment. However, nuclear
translocation of NF-kappaB p65 was not observed after HDAC treatment of
Jurkat T cells and even though we could effectively inhibit p65
expression by siRNA, it did not modify MICA/B expression. To identify
important elements in MICA regulation, we made a promoter construct
consisting of approximately 3 kb of the proximal MICA promoter in front
of GFP. Deletion analysis showed that a germinal center-box containing a
putative Sp1 site from position -113 to -93 relative to the mRNA start
site was important for HDAC and CMV-induced promoter activity. Sp1 was
subsequently shown to be important, as targeted mutation of the Sp1
binding sequence or siRNA mediated down modulation of Sp1-inhibited MICA
promoter activity and surface-expression.

Publication Types:
* Research Support, Non-U.S. Gov't

PMID: 18056367

J Gen Virol. 2007 Dec;88(Pt 12):3214-23.

Functional interaction of the human cytomegalovirus IE2 protein with
histone deacetylase 2 in infected human fibroblasts.
Park JJ, Kim YE, Pham HT, Kim ET, Chung YH, Ahn JH.
Department of Molecular Cell Biology, Samsung Biomedical Research
Institute, Sungkyunkwan University School of Medicine, Suwon, Republic
of Korea.

In human cytomegalovirus (HCMV)-infected cells, the 86 kDa
immediate-early (IE) 2 protein plays a key role in transactivating
downstream viral genes. Recently, IE2 has been shown to interact with
histone deacetylase 1 (HDAC1) and HDAC3. HDAC1 recruited by IE2 was
required for IE2-mediated autorepression of the major IE (MIE) promoter,
whereas IE2-HDAC3 interaction was suggested to relieve the repressive
effect of HDAC3 on viral early promoters. However, whether IE2 indeed
inhibits HDAC's deacetylation activity on viral promoters and interacts
with other HDACs remains unclear. Here, we provide evidence that IE2
functionally interacts with HDAC2 and negates its repressive effect on
the viral polymerase promoter. IE2 interacted with HDAC2 in both
virus-infected cells and in vitro, and required the conserved C-terminal
half for HDAC2 binding. The subcellular localization of HDAC2 was
changed in virus-infected cells, showing colocalization with IE2 in
viral transcription and replication sites. The overall HDAC2 protein
levels and its deacetylation activity slightly increased during the late
stages of infection and the IE2-associated deacetylation activity was
still sensitive to an HDAC inhibitor, trichostatin A. In transfection
assays, however, histone acetylation of the viral polymerase promoter
was suppressed by HDAC2, and this was relieved by IE2 binding.
Therefore, our data demonstrate that IE2 functionally interacts with
HDAC2 and modulates its deacetylation activity on the viral polymerase
promoter. Our results also support the idea that interactions of IE2
with several HDACs to modulate the host epigenetic regulation on viral
MIE and early promoters are important events in the process of
productive infection.

Publication Types:
* Research Support, Non-U.S. Gov't

PMID: 18024889

J Virol. 2007 Dec;81(23):13248-53. Epub 2007 Sep 19.
��
In vivo changes in the patterns of chromatin structure associated with
the latent herpes simplex virus type 1 genome in mouse trigeminal
ganglia can be detected at early times after butyrate treatment.

Neumann DM, Bhattacharjee PS, Giordani NV, Bloom DC, Hill JM.
Department of Ophthalmology (LSU Eye Center of Excellence), Louisiana
State University Health Sciences Center, New Orleans, Louisiana 70112,
USA.

During herpes simplex virus type 1 (HSV-1) latency in mouse dorsal root
ganglia (DRG), chromatin associated with the latency-associated
transcript (LAT) region of the viral genome is hyperacetylated at
lysines 9 and 14 of histone 3 [H3(K9, K14)], while lytic genes are
hypoacetylated. Explanted DRG exhibit a pattern of deacetylation of the
LAT enhancer followed by acetylation of the ICP0 promoter at early times
postexplant. Recently, we reported that sodium butyrate induced in vivo
reactivation of HSV-1 in latent mice. In this study, we assessed the
effect of sodium butyrate on the chromatin patterns of latent and
butyrate-treated mouse trigeminal ganglia (TG) via chromatin
immunoprecipitation (ChIP). We detected deacetylation of acetyl H3(K9,
K14) of the LAT promoter and LAT enhancer regions as early as 0.5 h
post-butyrate treatment, and this deacetylation corresponded to an
increase in the acetylation of the lytic promoters ICP0 and ICP4 at 0.5
h and 1 h post-butyrate treatment, respectively. This is the first study
to combine in vivo reactivation with the examination of the HSV-1 genome
through ChIP assays at early times after the introduction of in vivo
reactivation stimuli.

Publication Types:
* Research Support, N.I.H., Extramural
* Research Support, Non-U.S. Gov't


PMID: 17881451