Anti-herpetic Medications and Reduced Risk of Dementia in Patients with Herpes Simplex Virus Infections—a Nationwide, Population-Based Cohort Study in Taiwan

This retrospective cohort study is to investigate the association
between herpes simplex virus (HSV) infections and dementia, and the
effects of anti-herpetic medications on the risk involved, using
Taiwan’s National Health Insurance Research Database (NHIRD). We
enrolled a total of 33,448 subjects, and identified 8362 with newly
diagnosed HSV infections and 25,086 randomly selected sex- and
age-matched controls without HSV infections in a ratio of 1:3, selected
from January 1, to December 31, 2000. A multivariable Cox proportional
hazards regression model was used to evaluate the risk of developing
dementia in the HSV cohort. This analysis revealed an adjusted hazard
ratio of 2.564 (95% CI: 2.351-2.795, P < 0.001)
for the development of dementia in the HSV-infected cohort relative to
the non-HSV cohort. Thus, patients with HSV infections may have a
2.56-fold increased risk of developing dementia. A risk reduction of
dementia development in patients affected by HSV infections was found
upon treatment with anti-herpetic medications (adjusted HR = 0.092 [95%
CI 0.079-0.108], P < 0.001).
Theusage of anti-herpetic medications in the treatment of HSV infections
was associated with a decreased risk of dementia. These findings could
be a signal to clinicians caring for patients with HSV infections.
Further research is, therefore, necessary to explore the underlying
mechanism(s) of these associations.

Glutamine suppresses herpes in mice and guinea pigs | National Institutes of Health (NIH)

 "Glutamine supplements can suppress reactivation of herpes simplex virus (HSV) in mice and guinea pigs, according to findings recently published in the Journal of Clinical Investigation. The research was conducted by scientists at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, and at the U.S. Food and Drug Administration."



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Cellular cholesterol facilitates the post-entry replication cycle of herpes simplex virus 1. - PubMed - NCBI

 Cholesterol is an essential component of cell membranes and is required for HSV-1 entry (1-3). Treatment of HSV-1-infected Vero cells with methyl beta-cyclodextrin from 2 - 9 hours post-entry reduced plaque numbers. Transport of incoming viral capsids to the nuclear periphery was unaffected by cholesterol reduction suggesting that cell cholesterol is important for the HSV-1 replicative cycle at a stage(s) beyond entry after the arrival of capsids at the nucleus. The synthesis and release of infectious HSV-1 and cell-to-cell spread of infection were all impaired in cholesterol-reduced cells. Propagation of HSV-1 on DHCR24-/- fibroblasts, which lack the desmosterol-to-cholesterol conversion enzyme, resulted in the generation of infectious, extracellular virions (HSVdes) that lack cholesterol and likely contain desmosterol. The specific infectivity (PFU per viral genome) of HSVchol and HSVdes were similar suggesting cholesterol or desmosterol in the HSV envelope support similar levels of infectivity. However, infected DHCR24-/- fibroblasts released ∼1 log less infectious HSVdes and ∼1.5 logs fewer particles compared to release of cholesterol-containing particles (HSVchol) from parental fibroblasts, suggesting that the hydrocarbon tail of cholesterol facilitates viral synthesis. Together, the results suggest multiple roles for cholesterol in the HSV-1 replicative cycle.Importance HSV-1 infections are associated with a wide range of clinical manifestations that are of public health importance. Cholesterol is a key player in the complex interaction between viral and cellular factors that allows HSV-1 to enter host cells and establish infection. Previous reports have demonstrated a role for cellular cholesterol in the entry of HSV-1 into target cells. Here, we employ both chemical treatment and cells that are genetically defined to synthesize only desmosterol to demonstrate that cholesterol is important at stages following the initial entry and transport of viral capsids to the nucleus. Viral protein expression, encapsidation of viral genome and the release of mature virions were impacted by the reduction of cellular cholesterol. Cholesterol was also critical for cell-to-cell spread of infection. These findings provide new insights into the cholesterol-dependence of HSV-1 replication.



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Using herpes drugs to slow down Alzheimer’s disease could become reality - Umeå University, Sweden

 Umeå University researchers, led by Hugo Lövheim at the Department of Community Medicine and Rehabilitation and the Unit of Geriatric Medicine, have launched a clinical study investigating the effect of herpes drugs on Alzheimer’s disease. For four weeks, 36 people with Alzheimer’s disease will be receiving treatment with Valaciklovir, a drug which specifically targets active herpes virus. Several investigations will be made before and after the treatment to measure the effects on fundamental Alzheimer’s disease processes. Moreover, the participants will be examined with brain imaging, which together with a tracer substance accumulating in cells with active herpes virus infection could potentially detect herpes virus infection in brain cells in people with Alzheimer’s disease.



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Herpes Simplex Virus Type 1 Neuronal Infection Elicits Cellular and Molecular Mechanisms of Neuroinflammation and Neurodegeneration in in vitro and in vivo Mice Models - IOS Press

Abstract: Herpes simplex virus type 1 (HSV-1) is a neurotropic virus able to establish a persistent latent infection in the host. Herpes simplex encephalitis (HSE) is associated with a high mortality rate and significant neurological, neuropsychological, and neurobehavioral sequelae, which afflict patients for life. Currently, it is unclear whether asymptomatic recurrent reactivations of HSV-1 occur in the central nervous systems in infected people, and if these events could lead to a progressive deterioration of neuronal function. In this context, HSV-1 constitutes an important candidate to be included among the risk factors for the development of Alzheimer’s disease. Our group have demonstrated that HSV-1 triggers neurodegenerative events in in vitro and in vivo induced neuronal infection, evidenced by increase in tau hyperphosphorylation and caspase-3 dependent cleavage of tau protein, resembling what occurs in neurodegenerative diseases. In addition, in an in vivo model, a reactivation episode during asymptomatic latency of HSV-1 infection in mice was accompanied by upregulation of neuroinflammatory markers (toll-like receptor-4, interferon α/β, and p-IRF3). Besides, previous reports have shown that HSV-1 inhibits apoptosis during early infection, but is pro-apoptotic during productive infection. Taking in consideration that the stress sensors AMPK and Sirt1 are involved in neuronal survival and neuroprotection, we hypothesized that HSV-1 could activate the AMPK/Sirt1 axis as a strategy to establish latency through inhibition of apoptosis and restoration of the energy status. Thus, we demonstrated that HSV-1 modulates the AMPK/Sirt1 axis differentially during infection, interfering with pro-apoptotic signaling and regulating mitochondrial biogenesis, pivotal processes in the lifetime of neurons in the central nervous system. In conclusion, our findings support the idea that HSV-1 could contribute to induce neurodegenerative processes in age-associated pathologies such as Alzheimer’s diseasAbstract: Herpes simplex virus type 1 (HSV-1) is a neurotropic virus able to establish a persistent latent infection in the host. Herpes simplex encephalitis (HSE) is associated with a high mortality rate and significant neurological, neuropsychological, and neurobehavioral sequelae, which afflict patients for life. Currently, it is unclear whether asymptomatic recurrent reactivations of HSV-1 occur in the central nervous systems in infected people, and if these events could lead to a progressive deterioration of neuronal function. In this context, HSV-1 constitutes an important candidate to be included among the risk factors for the development of Alzheimer’s disease. Our group have demonstrated that HSV-1 triggers neurodegenerative events in in vitro and in vivo induced neuronal infection, evidenced by increase in tau hyperphosphorylation and caspase-3 dependent cleavage of tau protein, resembling what occurs in neurodegenerative diseases. In addition, in an in vivo model, a reactivation episode during asymptomatic latency of HSV-1 infection in mice was accompanied by upregulation of neuroinflammatory markers (toll-like receptor-4, interferon α/β, and p-IRF3). Besides, previous reports have shown that HSV-1 inhibits apoptosis during early infection, but is pro-apoptotic during productive infection. Taking in consideration that the stress sensors AMPK and Sirt1 are involved in neuronal survival and neuroprotection, we hypothesized that HSV-1 could activate the AMPK/Sirt1 axis as a strategy to establish latency through inhibition of apoptosis and restoration of the energy status. Thus, we demonstrated that HSV-1 modulates the AMPK/Sirt1 axis differentially during infection, interfering with pro-apoptotic signaling and regulating mitochondrial biogenesis, pivotal processes in the lifetime of neurons in the central nervous system. In conclusion, our findings support the idea that HSV-1 could contribute to induce neurodegenerative processes in age-associated pathologies such as Alzheimer’s disease

Microbes and Alzheimer’s Disease - IOS Press

We are researchers and clinicians working on Alzheimer’s disease (AD) or related topics, and we write to express our concern that one particular aspect of the disease has been neglected, even though treatment based on it might slow or arrest AD progression. We refer to the many studies, mainly on humans, implicating specific microbes in the elderly brain, notably herpes simplex virus type 1 (HSV1), Chlamydia pneumoniae, and several types of spirochaete, in the etiology of AD [1–4]. Fungal infection of AD brain [5, 6] has also been described, as well as abnormal microbiota in AD patient blood [7]. The first observations of HSV1 in AD brain were reported almost three decades ago [8]. The ever-increasing number of these studies (now about 100 on HSV1 alone) warrants re-evaluation of the infection and AD concept.

......................................Given the failure of the 413 trials of other types of therapy for AD carried out in the period 2002–2012 [78], antiviral/antimicrobial treatment of AD patients, notably those who are APOE ɛ 4 carriers, could rectify the ‘no drug works’ impasse. We propose that further research on the role of infectious agents in AD causation, including prospective trials of antimicrobial therapy, is now justified.

Protective Effect of Amyloid-β Peptides Against Herpes Simplex Virus-1 Infection in a Neuronal Cell Culture Model - IOS Press

Senile amyloid plaques are one of the main hallmarks of Alzheimer’s disease (AD). They correspond to insoluble deposits of amyloid-β peptides (Aβ) and are responsible for the inflammatory response and neurodegeneration that lead to loss of memory. Recent data suggest that Aβ possess antimicrobial and anti-viral activity in vitro. Here, we have used cocultures of neuroglioma (H4) and glioblastoma (U118-MG) cells as a minimal in vitro model to investigate whether Aβ is produced by neuroglioma cells and whether this could result in protective anti-viral activity against HSV-1 infection. Results showed that H4 cells secreted Aβ 42 in response to HSV-1 challenge and that U118-MG cells could rapidly internalize Aβ 42. Production of pro-inflammatory cytokines TNFα and IL-1β by H4 and U118-MG cells occurred under basal conditions but infection of the cells with HSV-1 did not significantly upregulate production. Both cell lines produced low levels of IFNα. However, extraneous Aβ 42 induced strong production of these cytokines. A combination of Aβ 42 and HSV-1 induced production of pro-inflammatory cytokines TNFα and IL-1β, and IFNα in the cell lines. The reported anti-viral protection of Aβ 42 was revealed in transfer experiments involving conditioned medium (CM) of HSV-1-infected H4 cells. CM conferred Aβ-dependent protection against HSV-1 replication in de novo cultures of H4 cells challenged with HSV-1. Type 1 interferons did not play a role in these assays. Our data established that H4 neuroglioma cells produced Aβ 42 in response to HSV-1 infection thus inhibiting secondary replication. This mechanism may play a role in the etiology of AD.

Herpes simplex and neurodegeneration (SFN abstracts)

Herpes Simplex Virus type-1 infection induces synaptic dysfunction in cultured cortical neurons via GSK-3 activation and intraneuronal amyloid-β pr... - PubMed - NCBI

Increasing evidence suggests that recurrent Herpes Simplex Virus type 1 (HSV-1) infection spreading to the CNS is a risk factor for Alzheimer's Disease (AD) but the underlying mechanisms have not been fully elucidated yet. Here we demonstrate that in cultured mouse cortical neurons HSV-1 induced Ca(2+)-dependent activation of glycogen synthase kinase (GSK)-3. This event was critical for the HSV-1-dependent phosphorylation of amyloid precursor protein (APP) at Thr668 and the following intraneuronal accumulation of amyloid-β protein (Aβ). HSV-1-infected neurons also exhibited: i) significantly reduced expression of the presynaptic proteins synapsin-1 and synaptophysin; ii) depressed synaptic transmission. These effects depended on GSK-3 activation and intraneuronal accumulation of Aβ. In fact, either the selective GSK-3 inhibitor, SB216763, or a specific antibody recognizing Aβ (4G8) significantly counteracted the effects induced by HSV-1 at the synaptic level. Moreover, in neurons derived from APP KO mice and infected with HSV-1 Aβ accumulation was not found and synaptic protein expression was only slightly reduced when compared to wild-type infected neurons. These data further support our contention that HSV-1 infections spreading to the CNS may contribute to AD phenotype.

β-Amyloid peptides display protective activity against the human Alzheimer's disease-associated herpes simplex virus-1.

Amyloid plaques, the hallmark of Alzheimer's disease (AD), contain fibrillar β-amyloid (Aβ) 1-40 and 1-42 peptides. Herpes simplex virus 1 (HSV-1) has been implicated as a risk factor for AD and found to co-localize within amyloid plaques. Aβ 1-40 and Aβ 1-42 display anti-bacterial, anti-yeast and anti-viral activities. Here, fibroblast, epithelial and neuronal cell lines were exposed to Aβ 1-40 or Aβ 1-42 and challenged with HSV-1. Quantitative analysis revealed that Aβ 1-40 and Aβ 1-42 inhibited HSV-1 replication when added 2 h prior to or concomitantly with virus challenge, but not when added 2 or 6 h after virus addition. In contrast, Aβ 1-40 and Aβ 1-42 did not prevent replication of the non-enveloped human adenovirus. In comparison, antimicrobial peptide LL-37 prevented HSV-1 infection independently of its sequence of addition. Our findings showed also that Aβ 1-40 and Aβ 1-42 acted directly on HSV-1 in a cell-free system and prevented viral entry into cells. The sequence homology between Aβ and a proximal transmembrane region of HSV-1 glycoprotein B suggested that Aβ interference with HSV-1 replication could involve its insertion into the HSV-1 envelope. Our data suggest that Aβ peptides represent a novel class of antimicrobial peptides that protect against neurotropic enveloped virus infections such as HSV-1. Overproduction of Aβ peptide to protect against latent herpes viruses and eventually against other infections, may contribute to amyloid plaque formation, and partially explain why brain infections play a pathogenic role in the progression of the sporadic form of AD.

Direct evidence of viral infection and mitochondrial alterations in the brain of fetuses at high risk for schizophrenia | Segundo Mesa Castillo | Psychiatric Hospital of Havana, Cuba | Infectious Diseases-2015 | OMICS International

The neurodevelopmental theory in the aetiology of schizophrenia is
considered one of the most consistent at present. Evidence from
epidemiological and neuropathological studies indicates that the
pathogenic process that culminate in the development of schizophrenia
are initiated early in life and has been associated with a variety of
prenatal environmental insults to the developing brain, including
infection. Although the infectious agents have been proposed as one of
the risk factors for schizophrenia the data on the association of a
specific infectious agent with prenatal brain evidence is absent.
Understanding of the structural abnormalities would allow a better
identification of neurodevelopmental processes that contribute to risk
for schizophrenia. We have hypothesized that at ultra high-risk fetuses
would have alterations at cellular level that would let us differentiate
them to the comparison subjects. A reappraisal of our ultrastructural
studies carried out in samples of the left temporal lobe of foetuses at
ultra high risk of developing schizophrenia is presented. The findings
obtained are compatible with an active infection of the central nervous
system by herpes simplex hominis type I [HSV1] virus. The present
results are the first direct evidence that demonstrate the presence of
this virus in the central nervous system of foetuses from schizophrenic
mothers in the critical period of foetal development. The importance of
this finding can have practical applications in the prevention of the
illness keeping in mind its direct relation to the aetiology and
physiopathology of schizophrenia. - See more at:
http://infection.omicsgroup.com/abstract/2015/direct-evidence-of-viral-infection-and-mitochondrial-alterations-in-the-brain-of-fetuses-at-high-risk-for-schizophrenia#sthash.E7Wj586W.dpuf

The
neurodevelopmental theory in the aetiology of schizophrenia is
considered one of the most consistent at present. Evidence from
epidemiological and neuropathological studies indicates that the
pathogenic process that culminate in the development of schizophrenia
are initiated early in life and has been associated with a variety of
prenatal environmental insults to the developing brain, including
infection. Although the infectious agents have been proposed as one of
the risk factors for schizophrenia the data on the association of a
specific infectious agent with prenatal brain evidence is absent.
Understanding of the structural abnormalities would allow a better
identification of neurodevelopmental processes that contribute to risk
for schizophrenia. We have hypothesized that at ultra high-risk fetuses
would have alterations at cellular level that would let us differentiate
them to the comparison subjects. A reappraisal of our ultrastructural
studies carried out in samples of the left temporal lobe of foetuses at
ultra high risk of developing schizophrenia is presented. The findings
obtained are compatible with an active infection of the central nervous
system by herpes simplex hominis type I [HSV1] virus. The present
results are the first direct evidence that demonstrate the presence of
this virus in the central nervous system of foetuses from schizophrenic
mothers in the critical period of foetal development. The importance of
this finding can have practical applications in the prevention of the
illness keeping in mind its direct relation to the aetiology and
physiopathology of schizophrenia. - See more at:
http://infection.omicsgroup.com/abstract/2015/direct-evidence-of-viral-infection-and-mitochondrial-alterations-in-the-brain-of-fetuses-at-high-risk-for-schizophrenia#sthash.E7Wj586W.dpuf

The
neurodevelopmental theory in the aetiology of schizophrenia is
considered one of the most consistent at present. Evidence from
epidemiological and neuropathological studies indicates that the
pathogenic process that culminate in the development of schizophrenia
are initiated early in life and has been associated with a variety of
prenatal environmental insults to the developing brain, including
infection. Although the infectious agents have been proposed as one of
the risk factors for schizophrenia the data on the association of a
specific infectious agent with prenatal brain evidence is absent.
Understanding of the structural abnormalities would allow a better
identification of neurodevelopmental processes that contribute to risk
for schizophrenia. We have hypothesized that at ultra high-risk fetuses
would have alterations at cellular level that would let us differentiate
them to the comparison subjects. A reappraisal of our ultrastructural
studies carried out in samples of the left temporal lobe of foetuses at
ultra high risk of developing schizophrenia is presented. The findings
obtained are compatible with an active infection of the central nervous
system by herpes simplex hominis type I [HSV1] virus. The present
results are the first direct evidence that demonstrate the presence of
this virus in the central nervous system of foetuses from schizophrenic
mothers in the critical period of foetal development. The importance of
this finding can have practical applications in the prevention of the
illness keeping in mind its direct relation to the aetiology and
physiopathology of schizophrenia. - See more at:
http://infection.omicsgroup.com/abstract/2015/direct-evidence-of-viral-infection-and-mitochondrial-alterations-in-the-brain-of-fetuses-at-high-risk-for-schizophrenia#sthash.E7Wj586W.dpuf

Herpes Simplex Virus Type 1 and Other Pathogens are Key Causative Factors in Sporadic Alzheimer’s Disease - IOS Press

This review focuses on research in epidemiology, neuropathology, molecular biology, and genetics regarding the hypothesis that pathogens interact with susceptibility genes and are causative in sporadic Alzheimer’s disease (AD). Sporadic AD is a complex multifactorial neurodegenerative disease with evidence indicating coexisting multi-pathogen and inflammatory etiologies. There are significant associations between AD and various pathogens, including Herpes simplex virus type 1 (HSV-1), Cytomegalovirus, and other Herpesviridae, Chlamydophila pneumoniae, spirochetes, Helicobacter pylori, and various periodontal pathogens. These pathogens are able to evade destruction by the host immune system, leading to persistent infection. Bacterial and viral DNA and RNA and bacterial ligands increase the expression of pro-inflammatory molecules and activate the innate and adaptive immune systems. Evidence demonstrates that pathogens directly and indirectly induce AD pathology, including amyloid-β (Aβ) accumulation, phosphorylation of tau protein, neuronal injury, and apoptosis. Chronic brain infection with HSV-1, Chlamydophila pneumoniae, and spirochetes results in complex processes that interact to cause a vicious cycle of uncontrolled neuroinflammation and neurodegeneration. Infections such as Cytomegalovirus, Helicobacter pylori, and periodontal pathogens induce production of systemic pro-inflammatory cytokines that may cross the blood-brain barrier to promote neurodegeneration. Pathogen-induced inflammation and central nervous system accumulation of Aβ damages the blood-brain barrier, which contributes to the pathophysiology of AD. Apolipoprotein E4 (ApoE4) enhances brain infiltration by pathogens including HSV-1 and Chlamydophila pneumoniae. ApoE4 is also associated with an increased pro-inflammatory response by the immune system. Potential antimicrobial treatments for AD are discussed, including the rationale for antiviral and antibiotic clinical trials.

Nutraceutical activators of AMPK/Sirt1 axis inhibit viral production and protect neurons from neurodegenerative events triggered during HSV-1 infection

Herpes simplex virus type-1 (HSV-1) is ubiquitous and is able to establish a
lifelong persistent latent infection in neurons of infected individuals. It has
been estimated that in approximately 70% of the population over 50 years old, the virus enters the brain and infects neurons, and possibly undergoes recurrent
reactivation episodes during lifetime, especially in immunodepressed individuals.
We previously showed that the sensors AMP-dependent kinase (AMPK) and Sirtuin 1 (Sirt1), involved in survival pathways and neuroprotection, were affected during the course of HSV-1 infection. To evaluate if natural activators of the AMPK/Sirt1 axis, such as Resveratrol and Quercetin could reduce viral propagation and/or counteract the effects of neuronal infection, we analyzed progeny virion production, neuronal viability and neurodegenerative events during HSV-1 infection. We found that the activators of AMPK/Sirt1 axis, increased the viability of infected neurons, significantly reduced the viral titer in the supernatant and the expression of viral genes. More importantly, pretreatment of neurons with Resveratrol or Quercetin significantly reduced the levels of
caspase-3 cleaved- and hyperphosphorylated tau associated with HSV-1 infection. These results suggest that activators of the AMPK/Sirt1 axis could be potentially useful in reducing the risk of HSV-1 productive infection in neurons and the cellular damage associated with reactivation episodes.

Related articles

Resveratrol inhibition of herpes simplex virus replication (1999).

Herpes simplex virus type 1 infection in neurons leads to production and nuclear localization of APP intracellular domain (AICD): implications for Alzheimer's disease pathogenesis.

Several data indicate that neuronal infection with herpes simplex virus
type 1 (HSV-1) causes biochemical alterations reminiscent of Alzheimer's
disease (AD) phenotype. They include accumulation of amyloid-β (Aβ),
which originates from the cleavage of amyloid precursor protein (APP),
and hyperphosphorylation of tau protein, which leads to neurofibrillary
tangle deposition. HSV-1 infection triggers APP processing and drives
the production of several fragments including APP intracellular domain
(AICD) that exerts transactivating properties. Herein, we analyzed the
production and intracellular localization of AICD following HSV-1
infection in neurons. We also checked whether AICD induced the
transcription of two target genes, neprilysin (nep) and glycogen
synthase kinase 3β (gsk3β), whose products play a role in Aβ clearance
and tau phosphorylation, respectively. Our data indicate that HSV-1 led
to the accumulation and nuclear translocation of AICD in neurons.
Moreover, results from chromatin immunoprecipitation assay showed that
AICD binds the promoter region of both nep and gsk3β. Time course
analysis of NEP and GSK3β expression at both mRNA and protein levels
demonstrated that they are differently modulated during infection. NEP
expression and enzymatic activity were initially stimulated but, with
the progression of infection, they were down-regulated. In contrast,
GSK3β expression remained nearly unchanged, but the analysis of its
phosphorylation suggests that it was inactivated only at later stages of
HSV-1 infection. Thus, our data demonstrate that HSV-1 infection
induces early upstream events in the cell that may eventually lead to Aβ
deposition and tau hyperphosphorylation and further suggest HSV-1 as a
possible risk factor for AD.

Radical Vaccine Design Effective Against Herpes Viruses | HHMI.org

Herpes simplex virus infections are an enormous global health problem and there is currently no viable vaccine. For nearly three decades, immunologists’ efforts to develop a herpes vaccine have centered on exploiting a single protein found on the virus’s outer surface that is known to elicit robust production of antibodies. Breaking from this approach, Howard Hughes Medical Institute (HHMI) scientists at Albert Einstein College of Medicine have created a genetic mutant lacking that protein. The result is a powerfully effective vaccine against herpes viruses.

“We have a very promising new candidate for herpes,” says William Jacobs, an HHMI investigator at the Albert Einstein College of Medicine, “but this might also be a good candidate as a vaccine vector for other mucosal diseases, particularly HIV and tuberculosis.”

The new vaccine was found to be effective against the two most common forms of herpes that cause cold sores (HSV-1) and genital ulcers (HSV-2). Both are known to infect the body’s nerve cells, where the virus can lay dormant for years before symptoms reappear. The new vaccine is the first to prevent this type of latent infection. “With herpes sores you continually get them,” Jacobs says. “If our vaccine works in humans as it does in mice, administering it early in life could completely eliminate herpes latency.” Jacobs and his colleagues reported their findings on March 10, 2015, in the journal eLife.

eLIFE paper 
Herpes simplex type 2 virus deleted in glycoprotein D protects against vaginal, skin and neural disease 

β-Amyloid peptides display protective activity against the human Alzheimer’s disease-associated herpes simplex virus-1 - Online First - Springer

Amyloid plaques, the hallmark of Alzheimer’s disease (AD), contain
fibrillar β-amyloid (Aβ) 1-40 and 1-42 peptides. Herpes simplex virus 1 (HSV-1)
has been implicated as a risk factor for AD and found to co-localize
within amyloid plaques. Aβ 1-40 and Aβ 1-42 display anti-bacterial,
anti-yeast and anti-viral activities. Here, fibroblast, epithelial and
neuronal cell lines were exposed to Aβ 1-40 or Aβ 1-42 and challenged
with HSV-1. Quantitative analysis revealed that Aβ 1-40 and Aβ 1-42 inhibited HSV-1
replication when added 2 h prior to or concomitantly with virus
challenge, but not when added 2 or 6 h after virus addition. In
contrast, Aβ 1-40 and Aβ 1-42 did not prevent replication of the
non-enveloped human adenovirus. In comparison, antimicrobial peptide
LL-37 prevented HSV-1 infection independently of its sequence of addition. Our findings showed also that Aβ 1-40 and Aβ 1-42 acted directly on HSV-1
in a cell-free system and prevented viral entry into cells. The
sequence homology between Aβ and a proximal transmembrane region of HSV-1 glycoprotein B suggested that Aβ interference with HSV-1 replication could involve its insertion into the HSV-1
envelope. Our data suggest that Aβ peptides represent a novel class of
antimicrobial peptides that protect against neurotropic enveloped virus
infections such as HSV-1.
Overproduction of Aβ peptide to protect against latent herpes viruses
and eventually against other infections, may contribute to amyloid
plaque formation, and partially explain why brain infections play a
pathogenic role in the progression of the sporadic form of AD.

Related articles

• Reactivated herpes simplex infection increases the risk of Alzheimer's disease. (polygenicpathways.blogspot.com)
• 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.
   

Amyloid beta reduces cytopathic effects of Herpes Simplex virus type I

Alzheimer’s disease (AD) is a neurodegenerative disorder that is
characterized by memory loss and other types of dementia. Amyloid β (Aβ)
is a main cause of senile plaques detected in the brains of patients
with AD and other forms of dementia. Recent evidence suggests that the
buildup of Aβ is may be in response to microbial infections in the
central nervous system. Aβ has been shown to inhibit the growth of
bacteria and yeast; however, little work has tested its role in reducing
viral activity. The present work tests the hypothesis that Aβ
suppresses the cytopathic effects induced by the neurotropic Herpes
Simplex Virus Type I (HSV-1). To test this hypothesis, we treated
SH-SY5Y neuroblastoma cells with varying concentrations of Aβ one hour
before HSV-1 infection (1716 strain). Forty-eight hours after infection,
cell viability and morphology was assayed. First we determined cell
viability by utilizing the
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)
assay. The MTT assay indicated that pretreatment of Aβ (100nM, 1μM,
10μM) reduced HSV-1 induced cell death by 40% (p<0.01).
Photomicrographs of neuroblastoma cells infected with HSV-1
(multiplicity of infection; MOI=1) also demonstrated that Aβ
pretreatment reduced cytopathic effects of HSV-1. To more directly test
HSV-1 activity, plaque formation assays are ongoing. These data indicate
that the antimicrobial activities of Aβ are not limited to bacteria.
Overall, the results provide another link connecting HSV-1 infection and
the progression of AD.

Relationship between herpes simplex virus-1-specific antibody titers and cortical brain damage in Alzheimer’s disease and amnestic mild cognitive impairment

Alzheimer’s disease (AD) is a multifactorial disease with a still barely
understood etiology. Herpes simplex virus 1 (HSV-1) has long been
suspected to play a role in the pathogenesis of AD because of its
neurotropism, high rate of infection in the general population, and
life-long persistence in neuronal cells, particularly in the same brain
regions that are usually altered in AD. The goal of this study was to
evaluate HSV-1-specific humoral immune responses in patients with a
diagnosis of either AD or amnestic mild cognitive impairment (aMCI), and
to verify the possible relation between HSV-1-specific antibody (Ab)
titers and cortical damage; results were compared to those obtained in a
group of healthy controls (HC). HSV-1 serum IgG titers were measured in
225 subjects (83 AD, 68 aMCI, and 74 HC). HSV-specific Ab avidity and
cortical gray matter volumes analyzed by magnetic resonance imaging
(MRI) were evaluated as well in a subgroup of these individuals (44 AD,
23 aMCI, and 26 HC). Results showed that, whereas HSV-1 seroprevalence
and IgG avidity were comparable in the three groups, increased Ab titers
(p < 0.001) were detected in AD and aMCI compared to HC.
Positive significant correlations were detected in AD patients alone
between HSV-1 IgG titers and cortical volumes in orbitofrontal (region
of interest, ROI1 R_Sp0.56; p = 0.0001) and bilateral temporal cortices (ROI2 R_Sp0.57; p < 0.0001; ROI3 R_Sp0.48; p
= 0.001); no correlations could be detected between IgG avidity and MRI
parameters. Results herein suggest that a strong HSV-1-specific humoral
response could be protective toward AD-associated cortical damage.

Cold sores increase risk of dementia, research suggests -- ScienceDaily

Hugo Lövheim and Fredrik Elgh, professor at the Department of Virology,
have now confirmed this link in two large epidemiological studies. In
one study, which is based on the Betula project, a study on aging,
memory and dementia, the researchers show that a reactivated herpes
infection doubled the risk of developing Alzheimer's disease. This study
had 3,432 participants who were followed for 11.3 years on average. In
another study, samples donated to the Medical Biobank at Umeå University
from 360 people with Alzheimer's disease were examined and as many
matched people who had not developed dementia. The samples were taken on
average 9.6 years before diagnosis. This study showed an approximately
doubled risk of developing Alzheimer's disease if the person was a
carrier of the herpes virus.

Related articles

• Exposure to common infections linked to brain function decline (medicalnewstoday.com)
• Poor dental health may lead to Alzheimer's, study suggests (medicalnewstoday.com)

Titers of herpes simplex virus type 1 antibodies positively correlate with grey matter volumes in Alzheimer's disease.

HSV-1 infection of the central nervous system targets the same brain
regions most affected in Alzheimer's disease (AD) and could play a
pathogenic role in AD. HSV-1 serum IgG titers were analyzed in patients
with mild AD (n = 83) and healthy controls (HC, n = 51); results were
correlated with cortical grey matter (GM) volumes as analyzed by MRI.
Seroprevalence and antibody (Ab) titers were comparable between AD and
HC; elevated Ab titers (>75th percentile) were nevertheless
significantly more frequent in AD and were positively correlated with
cortical bilateral temporal and orbitofrontal GM volumes.
HSV-1-specific-Ab could possibly play a protective role in the early
stages of AD.