Herpes Simplex Virus (HSV-1)

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"Give with a free hand, but give only your own."
-- J.R.R. Tolkien The Children of Hurin
- Herpes Simplex Virus (HSV-1) -

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Observations:

New Evidence Found Linking Herpes And Alzheimer’s
ScienceDaily (May 12, 2000)
"Could Lead to New Treatments Targeting the Herpes Virus"

"Researchers have long suspected a connection between the herpes virus and Alzheimer’s disease. A new study provides a potential explanation that could lead to development of a vaccine to prevent the disease or new drugs to treat it, according to the researchers. The study appears in the May 16 issue of Biochemistry, a peer-reviewed publication of the American Chemical Society, the world’s largest scientific society."

"Researchers at the University of California, Irvine, demonstrated that a synthetic protein that resembles the herpes simplex 1 virus (HSV-1) mimics the structure and function of a protein called beta-amyloid, a toxic agent that accumulates in the brains of Alzheimer’s patients."

"Genetic sequencing revealed that two-thirds of a portion of the viral protein is identical to the beta-amyloid protein. The researchers showed that, like beta-amyloid, it could kill brain neurons, a key feature in the development of Alzheimer’s. Moreover, in laboratory experiments, the viral protein formed abnormal twisted fibers like those found in the brains of Alzheimer’s patients — the definitive hallmark of the disease..."
http://www.sciencedaily.com/releases/2000/05/000512083302.htm

Cold Sore Virus Might Play Role In Alzheimer's
ScienceDaily (Jan. 3, 2007)
"A gene known to be a major risk factor for Alzheimer's disease puts out the welcome mat for the virus that causes cold sores, allowing the virus to be more active in the brain compared to other forms of the gene..."
http://www.sciencedaily.com/releases/2007/01/070103110103.htm

Alzheimer’s Disease Vaccine on the Horizon
December 15, 2010
...Infectious agents are normally known for causing acute illnesses, but some have been implicated as the cause of chronic diseases, including human papillomavirus in cervical cancer and the bacterium Helicobacter pylori in stomach ulcers, which has led to the use of vaccines and antimicrobial agents to treat chronic diseases. In the last decade, Herpes simplex virus type 1 (HSV1) has been increasingly associated with the development of AD... HSV1 does not cause AD on its own. There are likely host factors that alter the risks for developing AD...
http://brainblogger.com/2010/12/15/alzheimer’s-disease-vaccine-on-the-horizon/

Curcumin inhibits herpes simplex virus immediate-early gene expression by a mechanism independent of p300/CBP histone acetyltransferase activity.
Virology. 2008 Apr 10;373(2):239-47. Epub 2008 Jan 14.
Kutluay SB, Doroghazi J, Roemer ME, Triezenberg SJ.

Graduate Program in Cell and Molecular Biology, Michigan State University, East Lansing, MI 48824, USA.
Abstract

Curcumin, a phenolic compound from the curry spice turmeric, exhibits a wide range of activities in eukaryotic cells, including antiviral effects that are at present incompletely characterized. Curcumin is known to inhibit the histone acetyltransferase activity of the transcriptional coactivator proteins p300 and CBP, which are recruited to the immediate early (IE) gene promoters of herpes simplex virus type 1 (HSV-1) by the viral transactivator protein VP16. We tested the hypothesis that curcumin, by inhibiting these coactivators, would block viral infection and gene expression. In cell culture assays, curcumin significantly decreased HSV-1 infectivity and IE gene expression. Entry of viral DNA to the host cell nucleus and binding of VP16 to IE gene promoters was not affected by curcumin, but recruitment of RNA polymerase II to those promoters was significantly diminished. However, these effects were observed using lower curcumin concentrations than those required to substantially inhibit global H3 acetylation. No changes were observed in histone H3 occupancy or acetylation at viral IE gene promoters. Furthermore, p300 and CBP recruitment to IE gene promoters was not affected by the presence of curcumin. Finally, disruption of p300 expression using a short hairpin RNA did not affect viral IE gene expression. These results suggest that curcumin affects VP16-mediated recruitment of RNA polymerase II to IE gene promoters by a mechanism independent of p300/CBP histone acetyltransferase activity.

PMID: 18191976 [PubMed]
http://www.ncbi.nlm.nih.gov/pubmed/18191976
Free full Text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2668156/?tool=pubmed

The Pathogen Hypothesis (Live Discussion on www.alzforum.org)
Moderator’s summary: Pathogens as a cause of Alzheimer’s disease
By June Kinoshita

The notion that microbes such as herpes simplex virus 1 (HSV1) and Chlamydophila pneumoniae (Cp) could be a causal factor in Alzheimer’s diseases would probably be viewed by the main stream of AD researchers as being beyond the pale. Although a small body of recent findings has reported strikingly strong associations between these pathogens and AD [1,7], subsequent attempts to replicate the findings have met with mixed results (discussed in [10]). At this juncture, it might be convenient to dismiss the hypothesis, but as both sides of this debate session agreed, there are plausible reasons for these discrepancies that deserve to be resolved through further research. While opinions diverged on the strength of evidence for and against the hypothesis, there was a consensus that the possibility of common infectious agents causing such a widespread scourge of old age is one that is too important to ignore.
http://www.alzforum.org/res/for/journal/balin/default.asp

Another Look at Herpes Simplex
Chronic Flare-Ups Pose Harm to Brain
Cincinnati Children's Hospital Medical Center
Fall 2010
A virus that most of us carry but think little about should probably make us think twice, says Nancy Sawtell, PhD.

Sawtell, a researcher in the Division of Infectious Diseases, has been studying herpes simplex virus (HSV) for two decades. She, together with her collaborator Richard Thompson, PhD, at the University of Cincinnati College of Medicine, have discovered a number of things about the virus – and hope that what they have learned will change our largely cavalier attitude about it.

“This virus, which most of us have, has the potential to be wicked,” Sawtell says. “We have not done a good job educating people about it.” In fact, “wicked” might be an understatement. Once we contract HSV – and estimates are that between 70 and 90 percent of the world population has it – we can’t get rid of it. The virus remains latent in the nervous system for a lifetime, but periodically can flare up to cause anything from mild cold sores to genital rashes to encephalitis, blindness and even death. HSV may even have a link to Alzheimer’s disease, Sawtell says...

The Alzheimer's Connection

Sawtell wants to stop this lytic cycle because she has evidence that repeated inflammation caused by the virus harms the central nervous system.

“Having a latent virus that periodically reactivates in your central nervous system can’t be a good thing,” she says.

Sawtell is investigating whether repeated cycles of inflammation might lead to Alzheimer’s disease for some individuals. The idea was brought to her attention by British researcher Ruth Itzhaki, PhD.

“She had a hypothesis that carrying this chronic latent infection in your brain, when combined with a certain genetic background, represents a very high risk of developing Alzheimer’s,” Sawtell says.

By her own admission, Sawtell “was skeptical” about the idea. But Itzhaki’s research found that individuals who have a combination of latent HSV in the brain and the genetic variant APOE 4 have increased risk of acquiring Alzheimer’s disease. “And this work is fairly convincing” says Sawtell, “but demonstrating causality is difficult without an animal model.” So Sawtell began working with mice in which the human APOE 4 allele was knocked in, and infected them with HSV.

“A lot more virus got into the brains of the animals with the APOE 4 allele,” she says.

Sawtell also induced reactivation of the virus episodically over a long period of time to see what happened in the mouse’s central nervous system...
http://www.cincinnatichildrens.org/health/subscribe/ResearchHorizons/archives/2010/fall/herpes-simplex.htm

Apparently the nerves to the face originate deep in the brain. It is very conceivable that a cold sore outbreak on the skin could travel along the nerve path and back deep into the brain. The neurons have thousands of connections to other neurons and the virus could spread that way to other cells. See Dr. Ruth Itzhaki's research. It has shown the presence of DNA of the herpes virus in beta-amyloid plaques in people with APOE4 gene. For people without the APOE4 gene, it could be another infection or toxin that results in AD or other neurodegenerative diseases. The lauric acid in coconut oil also kills helicobacter pylori, candida and other fungi, and other viruses with lipid capsules, such as HIV and other members of the herpes virus family.

See refs at: http://www.coconutketones.com

Researchers link herpes to Alzheimer's disease
Physorg.com
April 4, 2011
Laboratories at the University of New Mexico (UNM), Brown University, and House Ear Institute (HEI) have developed a new technique to observe herpes simplex virus type 1 (HSV1) infections growing inside cells. HSV1, the cause of the common cold sore, persists in a latent form inside nerve cells. Re-activation and growth of HSV1 infections contribute to cognitive decline associated with Alzheimer's disease. Details are published in the March 31 issue of PLoS ONE magazine from the Public Library of Science.
http://www.physorg.com/news/2011-04-link-herpes-alzheimer-disease.html

Herpes Simplex Virus Dances with Amyloid Precursor Protein while Exiting the Cell
Cheng S-B, Ferland P, Webster P, Bearer EL (2011)
PLoS ONE 6(3): e17966. March 31, 2011
Abstract
Herpes simplex type 1 (HSV1) replicates in epithelial cells and secondarily enters local sensory neuronal processes, traveling retrograde to the neuronal nucleus to enter latency. Upon reawakening newly synthesized viral particles travel anterograde back to the epithelial cells of the lip, causing the recurrent cold sore. HSV1 co-purifies with amyloid precursor protein (APP), a cellular transmembrane glycoprotein and receptor for anterograde transport machinery that when proteolyzed produces A-beta, the major component of senile plaques. Here we focus on transport inside epithelial cells of newly synthesized virus during its transit to the cell surface. We hypothesize that HSV1 recruits cellular APP during transport. We explore this with quantitative immuno-fluorescence, immuno-gold electron-microscopy and live cell confocal imaging. After synchronous infection most nascent VP26-GFP-labeled viral particles in the cytoplasm co-localize with APP (72.8+/−6.7%) and travel together with APP inside living cells (81.1+/−28.9%). This interaction has functional consequences: HSV1 infection decreases the average velocity of APP particles (from 1.1+/−0.2 to 0.3+/−0.1 µm/s) and results in APP mal-distribution in infected cells, while interplay with APP-particles increases the frequency (from 10% to 81% motile) and velocity (from 0.3+/−0.1 to 0.4+/−0.1 µm/s) of VP26-GFP transport. In cells infected with HSV1 lacking the viral Fc receptor, gE, an envelope glycoprotein also involved in viral axonal transport, APP-capsid interactions are preserved while the distribution and dynamics of dual-label particles differ from wild-type by both immuno-fluorescence and live imaging. Knock-down of APP with siRNA eliminates APP staining, confirming specificity. Our results indicate that most intracellular HSV1 particles undergo frequent dynamic interplay with APP in a manner that facilitates viral transport and interferes with normal APP transport and distribution. Such dynamic interactions between APP and HSV1 suggest a mechanistic basis for the observed clinical relationship between HSV1 seropositivity and risk of Alzheimer's disease.
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0017966

Herpes Linked to Alzheimer's Disease: 'Cold Sores' Connected to Cognitive Decline

ScienceDaily (Apr. 4, 2011) — Laboratories at the University of New Mexico (UNM), Brown University, and House Ear Institute (HEI) have developed a new technique to observe herpes simplex virus type 1 (HSV1) infections growing inside cells. HSV1, the cause of the common cold sore, persists in a latent form inside nerve cells. Re-activation and growth of HSV1 infections contribute to cognitive decline associated with Alzheimer's disease...
http://www.sciencedaily.com/releases/2011/04/110404122203.htm

Shi-Bin Cheng, Paulette Ferland, Paul Webster, Elaine L. Bearer. Herpes Simplex Virus Dances with Amyloid Precursor Protein while Exiting the Cell. PLoS ONE, 2011; 6 (3): e17966 DOI: 10.1371/journal.pone.0017966

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References:

[There has been some speculation that the HSV-1 virus is involved with AD since its RNA has been found typically found at the center of the amyoid-beta plaques. Would such a strategy as this used for HIV be able to “purge” the cells of dormant HSV???]

Pioneering Study Shows Drug Can Purge Dormant HIV
ScienceDaily (July 25, 2012)
http://www.sciencedaily.com/releases/2012/07/120725132204.htm
http://news.unchealthcare.org/news/2012/july/pioneering-study-shows-drug-can-purge-dormant-hiv

Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy
N. M. Archin, A. L. Liberty, A. D. Kashuba, S. K. Choudhary, J. D. Kuruc, A. M. Crooks, D. C. Parker, E. M. Anderson, M. F. Kearney, M. C. Strain, D. D. Richman, M. G. Hudgens, R. J. Bosch, J. M. Coffin, J. J. Eron, D. J. Hazuda, D. M. Margolis.
Nature, 2012; 487 (7408): 482 DOI: 10.1038/nature11286
[No PubMed citation yet]

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