Temporal Cognitive Decline Associated With Exposure to Infectious Agents in a Population-based, Aging Cohort. - PubMed - NCBI

 "Numerous cross-sectional studies have related exposure to neurotropic infectious agents with cognitive dysfunction in older adults, however, the temporal sequence is uncertain.

METHODS:
In a representative, well-characterized, population-based aging cohort, we determined whether the temporal trajectories of multiple cognitive domains are associated with exposure to cytomegalovirus (CMV), Herpes Simplex virus, type 1 (HSV-1), Herpes Simplex virus, type 2 (HSV-2), or Toxoplasma gondii (TOX). Complex attention, executive functions, memory, language, and visuospatial function were assessed annually for 5 years among consenting individuals. Study entry IgG antibody titers indexing exposure to each infectious agent were examined in relation to slopes of subsequent temporal cognitive decline using multiple linear regressions adjusted for potential confounders.

RESULTS:
The IgG levels for HSV-2 were significantly associated with baseline cognitive domain scores (N=1022 participants). Further, the IgG levels for HSV-2, TOX, and CMV, but not HSV-1 were significantly associated with greater temporal cognitive decline that varied by type of infection.

CONCLUSIONS:
Exposure to CMV, HSV-2, or TOX is associated with cognitive deterioration in older individuals, independent of general age-related variables. An increased understanding of the role of infectious agents in cognitive decline may lead to new methods for its prevention and treatment."



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PLOS ONE: Gene Expression Profiles from Disease Discordant Twins Suggest Shared Antiviral Pathways and Viral Exposures among Multiple Systemic Autoimmune Diseases

Viral agents are of interest as possible autoimmune triggers due to prior reported associations and widely studied molecular mechanisms of antiviral immune responses in autoimmunity. Here we examined new viral candidates for the initiation and/or promotion of systemic autoimmune diseases (SAID), as well as possible related signaling pathways shared in the pathogenesis of those disorders. RNA isolated from peripheral blood samples from 33 twins discordant for SAID and 33 matched, unrelated healthy controls was analyzed using a custom viral-human gene microarray. Paired comparisons were made among three study groups—probands with SAID, their unaffected twins, and matched, unrelated healthy controls—using statistical and molecular pathway analyses. Probands and unaffected twins differed significantly in the expression of 537 human genes, and 107 of those were associated with viral infections. These 537 differentially expressed human genes participate in overlapping networks of several canonical, biologic pathways relating to antiviral responses and inflammation. Moreover, certain viral genes were expressed at higher levels in probands compared to either unaffected twins or unrelated, healthy controls. Interestingly, viral gene expression levels in unaffected twins appeared intermediate between those of probands and the matched, unrelated healthy controls. Of the viruses with overexpressed viral genes, herpes simplex virus-2 (HSV-2) was the only human viral pathogen identified using four distinct oligonucleotide probes corresponding to three HSV-2 genes associated with different stages of viral infection. Although the effects from immunosuppressive therapy on viral gene expression remain unclear, this exploratory study suggests a new approach to evaluate shared viral agents and antiviral immune responses that may be involved in the development of SAID

Herpes simplex virus type 2 infection induces AD-like neurodegeneration markers in human neuroblastoma cells - Neurobiology of Aging

Herpes simplex virus (HSV) types 1 and 2 are neurotropic viruses that
establish lifelong latent infections in neurons. Mounting evidence
suggests that HSV-1 infection is involved in the pathogenesis of
Alzheimer’s disease (AD). The relationships between other herpesvirus
infections and events associated with neurodegeneration have not,
however, been extensively studied. The present work reports that HSV-2
infection leads to the strong accumulation of hyperphosphorylated tau
and the amyloid-β peptides Aβ40 and Aβ42 (all major pathological
hallmarks of AD) in human SK-N-MC neuroblastoma cells. Infection is also
associated with a marked reduction in the amount of Aβ40 secreted, and
in the proteolytic fragments of the amyloid-β precursor protein (APP)
(secreted APPα and the α-C-terminal fragment). These results indicate
that HSV-2 infection inhibits the non-amyloidogenic pathway of APP
processing and impairs Aβ secretion in these cells. In addition, HSV-2
induces the accumulation of intracellular autophagic compartments
containing Aβ due to a failure in the late stages of autophagy. To our
knowledge, this is the first report to show that HSV-2 infection
strongly alters the tau phosphorylation state, APP processing, and
autophagic process in human neuroblastoma cells, leading to the
appearance of AD-like neurodegeneration markers.

CDK9 inhibitor FIT-039 prevents replication of multiple DNA viruses.

A wide range of antiviral drugs is currently available; however,
drug-resistant viruses have begun to emerge and represent a potential
public health risk. Here, we explored the use of compounds that inhibit
or interfere with the action of essential host factors to prevent virus
replication. In particular, we focused on the cyclin-dependent kinase 9
(CDK9) inhibitor, FIT-039, which suppressed replication of a broad
spectrum of DNA viruses through inhibition of mRNA transcription.
Specifically, FIT-039 inhibited replication of herpes simplex virus 1
(HSV-1), HSV-2, human adenovirus, and human cytomegalovirus in cultured
cells, and topical application of FIT-039 ointment suppressed skin
legion formation in a murine HSV-1 infection model. FIT-039 did not
affect cell cycle progression or cellular proliferation in host cells.
Compared with the general CDK inhibitor flavopiridol, transcriptome
analyses of FIT-039-treated cells revealed that FIT-039 specifically
inhibited CDK9. Given at concentrations above the inhibitory
concentration, FIT-039 did not have a cytotoxic effect on mammalian
cells. Importantly, administration of FIT-039 ameliorated the severity
of skin lesion formation in mice infected with an acyclovir-resistant
HSV-1, without noticeable adverse effects. Together, these data indicate
that FIT-039 has potential as an antiviral agent for clinical
therapeutics.

Genetic Factors Influence Serological Measures of Common Infections

"Our results demonstrate, for the first time for many of these pathogens (Chlamydophila pneumoniae, Helicobacter pylori, Toxoplasma gondii, hepatitis A virus, influenza A and B, cytomegalovirus, Epstein-Barr virus, herpes simplex virus (HSV)-1 and -2, human herpesvirus-6, and varicella zoster virus ), that individual genetic differences of the human host contribute substantially to antibody levels to many common infectious agents, providing impetus for the identification of underlying genetic variants, which may be of clinical importance."

See also: Human genetic susceptibility to infectious disease from Nature Reviews

Genetic Factors Influence Serological Measures of Common Infections.

The authors tested heritability for 13 common infections (Chlamydophila pneumoniae, Helicobacter pylori, Toxoplasma gondii, adenovirus 36 , hepatitis A virus, influenza A and B, cytomegalovirus, Epstein-Barr virus, herpes simplex virus (HSV)-1 and -2, human herpesvirus-6, and the varicella zoster virus. Different genetic factors  contribute to different infection.

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

Classical population genetics shows that varying permutations of genes and risk factors permit or disallow the effects of causative agents, depending on circumstance. For example, genes and environment determine whether a fox kills black or white rabbits on snow or black ash covered islands. Risk promoting effects are different on each island, but obscured by meta-analysis or GWAS data from both islands, unless partitioned by different contributory factors. In Alzheimer's disease, the foxes appear to be herpes, borrelia or chlamydial infection, hypercholesterolemia, hyperhomocysteinaemia, diabetes, cerebral hypoperfusion, oestrogen depletion, or vitamin A deficiency, all of which promote beta-amyloid deposition in animal models—without the aid of gene variants. All relate to risk factors and subsets of susceptibility genes, which condition their effects. All are less prevalent in convents, where nuns appear less susceptible to the ravages of ageing. Antagonism of the antimicrobial properties of beta-amyloid by Abeta autoantibodies in the ageing population, likely generated by antibodies raised to beta-amyloid/pathogen protein homologues, may play a role in this scenario. These agents are treatable by diet and drugs, vitamin supplementation, pathogen detection and elimination, and autoantibody removal, although again, the beneficial effects of individual treatments may be tempered by genes and environment.

Vitamin D status and antibody levels to common viruses in pediatric-onset multiple sclerosis.

An interesting interplay between vitamin D , immunity and virology in normal and multiple sclerosis patients

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In vitro anti HSV-1 and HSV-2 activity of Tanacetum vulgare extracts and isolated compounds: An approach to their mechanisms of action.

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Tanacetum vulgare, commonly known as tansy shows activity against HSV-1 and HSV-2

Virus Pathogen Database and Analysis Resource (ViPR) - Genome database with visualization and analysis tools

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Raltegravir could be valid target against all Herpesviridae

Raltegravir could be valid target against all Herpesviridae

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Phenoxazine Derivatives Suppress the Infections Caused by Herpes Simplex Virus Type-1 and Herpes Simplex Virus Type-2

Phenoxazine Derivatives

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The human genome is composed of viral DNA

Evidence from over 2 million viral/human alignments, shows that the human genome is composed of viral DNA.
This is not just retroviruses (XMRV and HIV-1) but common viruses such as the rhinovirus, Epstein-Barr, influenza, herpes, papillomavirus, coronavirus and many more. This supports the idea, proposed over a century ago, by J.B.S.Haldane and Felix D'Herelle that viruses are responsible for the origin of life, and also the idea that viral inserts are responsible for evolutionary jumps.(the insertion of several viral genes, if passed on through the germ line, effectively creates a new being)
As if that were not interesting enough, here is the important factor , exemplified by Alzheimer's disease  Bipolar disorder and schizophrenia. The insertion points of the viruses implicated as risk factors in any particular disease correspond to the locations of the genes implicated in the disease.
The more important the gene in Alzheimer's disease (and others), the more viral proteins it matches (and those of other pathogens).
These viral matches appear to cover the whole human genome, and every human protein is homologous to one virus or another.
In the human genome, these matches are characterised by millions of gapped consecutive and contiguous segments which translate into short contiguous peptide stretches (5-12 amino acids long).The older the viral insertion, the more fragmented the DNA, the shorter the protein matches,but the greater the number of human/viral homologues. 
These human protein matches (vatches) are identical to those in the proteins expressed by the viruses implicated in the disease.
Because the viral protein is similar to human receptors, peptide ligands, enzymes,  etc it can act as a dummy ligand or a decoy receptor, and also interfere with the interactome of its human counterpart. This is shown quite clearly in the DISC1/viral interactome
Upon infection, antibodies to the virus also risk targeting their human counterparts, which will in effect be knocked down when the antibody binds. The protein equivalent of gene knockouts. If the peptides are highly immunogenic, then cells containing the virus, or its human analogue will be targeted for destruction. This is exemplified by the fact that immunisation with tau in mice provokes the neurofibrillary tangle pathology seen in Alzheimer's disease.Tau is homologous to Herpes simplex and other viral proteins.
All of the diseases on the website pages Alzheimer's disease, Bipolar disorder, Schizophrenia, Chonic fatigue, and more, have an autoimmune component, pathogens are implicated in all, and the genes and pathogens fit together, hand in glove, for all (Bipolar disorder, Alzheimer's and schizophrenia).
Viruses (known and unsuspected culrits) are also homologous to the autoantigens in multiple sclerosis and to the mutant proteins in Huntington's disease and cystic fibrosis (see website)
This suggests that many human diseases work via this common mechanism, and therefore that most are preventable, by vaccination or elimination of the pathogen, and perhaps curable by immunosuppressant therapy.

The BLAST files are here

Examples of how this works are here
A pdf of a prepublication is available at NaturePrecedings.

Aquaporin 4 antibody positive central nervous system autoimmunity and multiple sclerosis are characterized by a distinct profile of antibodies to herpes viruses.

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Familial and late-onset Alzheimer's disease: Autoimmune disorders triggered by viral, microbial and allergen mimics of beta-amyloid and APP mutants ?

Beta-amyloid (Aβ) autoantibodies are common in Alzheimer’s disease. Some may be derived from Herpes simplex and from 68 other phages and viruses expressing proteins that exactly match an immunogenic and fibrillogenic VGGVV Aβ sequence.Many other viral, microbial and allergenic proteins (particularly from dust mites) align with Aβ as do proteins from Borrelia burgdoferi, C.Pneumoniae, H.Pylori or P.Gingivalis or S.Mutans that cause periodontitis and tooth loss which are associated with Alzheimer's disease  C.Neoformans which has been associated with a rare but curable form of the disorder also expresses proteins with homology toAβ . Immune-related proteins are present in amyloid plaques and the complement membrane attack complex in neurones in Alzheimer’s disease brains. Alzheimer’s disease may thus be an autoimmune disorder triggered by pathogenic antigens homologous to Aβ, whose antibodies target and kill Aβ containing neurones, via immune activation and complement-related lysis. This scenario explains many epidemiological observations in Alzheimer’s disease, which is more common in women and Afro-Americans, as is HSV-2 seroprevalence; related to the number of pregnancies (exposure to childhood infections) and less severe in nuns (low exposure to sexually transmitted diseases). Atopy and autoimmune disorders are common in Alzheimer’s disease in accord with allergen homology to Aβ, and anti-inflammatory agents reduce Alzheimer’s disease risk. Cancer-causing viruses (papillomavirus, hepatitis B, Epstein-Barr) and plant viruses from Mediterranean diet components align with the Aβ sequence targeted by catalytic autoantibodies, perhaps explaining the inverse association of diet and cancer with Alzheimer’s disease. As a papillomavirus vaccine already exists, it may have a role to play in Alzheimer’s disease. This scenario is also relevant to familial Alzheimer’s disease. Mutant forms of APP₇₁₇ and the Swedish mutant convert the surrounding peptide to matches with commensal bacteria (E.Coli, E. Faecalis, P.Gingivalis) and to viruses with very high seroprevalence (HHV-6, norovirus, influenza and the common cold). Late-onset and Familial Alzheimer’s disease may both be autoimmune disorders caused by diverse common pathogens and allergens homologous to Aβ or mutant APP fragments. Immunosuppressants, vaccination and pathogen elimination may be of benefit in both conditions.See Alzheimer's disease risk factors

Pubmed: Autoimmunity and Alzheimer's and Herpes

A Danish National Birth Cohort study of maternal HSV-2 antibodies as a risk factor for schizophrenia in their offspring.

HSV-2