Productive herpes simplex virus in brain of elderly normal subjects and Alzheimer's disease patients

Molecular Neurobiology Laboratory, Faculty of Life Sciences, The University of Manchester, Manchester, United Kingdom.
Journal of Medical Virology (Impact Factor: 2.35). 02/2005; 75(2):300-6. DOI: 10.1002/jmv.20271
Source: PubMed


It was previously shown that herpes simplex virus type 1 (HSV1) DNA resides latently in a high proportion of aged brains and that in carriers of the type 4 allele of the apolipoprotein E gene (APOE-epsilon4), it confers a strong risk of Alzheimer's disease. It was suggested that initial entry of brain by HSV1 and any subsequent reactivation(s) would cause a type of limited encephalitis, the resulting damage being more harmful in APOE-epsilon4 carriers. Reactivation(s) would induce synthesis of intrathecal antibodies; these are long-lived after herpes simplex encephalitis so they were sought in cerebrospinal fluid (CSF) of Alzheimer's disease patients and age-matched normal subjects. Intrathecal antibodies to human herpesvirus 6 (HHV6) were also sought as DNA of this virus has been detected previously in a high proportion of Alzheimer's disease brains. Antibody indices for HSV and HHV6 were measured using indirect ELISA for IgG antibody, and single radial immunodiffusion was used for albumin, in serum and CSF. A raised antibody index (>1.5) indicative of virus-specific intrathecal HSV1 IgG synthesis was found in 14/27 (52%) Alzheimer's disease patients and 9/13 (69%) age-matched normals (difference non-significant). A raised antibody index to HHV6 was detected in 22% of the Alzheimer's disease patients and in no normals, so presumably this virus either did not reactivate in brain or it elicited only short-lived intrathecal antibodies. The HSV1 results confirm the original PCR findings that show the presence of HSV1 DNA sequences in many elderly brains, and indicate also that the whole functional HSV1 genome is present, and that the virus has replicated.

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    • "Herpes simplex virus type-1 (HSV-1) is ubiquitous and is able to establish a lifelong persistent latent infection in neurons of infected individuals (Whitley and Roizman, 2002; Damasio and Van Hoesen, 1985; Jamieson et al., 1992; Saldanha et al., 1986). It has been estimated that in approximately 70% of the population over 50 years old, the virus enters the brain and infects neurons, suggesting the existence of recurrent reactivations (Wozniak et al., 2005). Accordingly , post-mortem PCR-based studies detected latent HSV-1 virus in the central nervous system (CNS) in a high percentage of brains. "
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    ABSTRACT: 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. Copyright © 2015. Published by Elsevier B.V.
    Virus Research 05/2015; 205. DOI:10.1016/j.virusres.2015.05.015 · 2.32 Impact Factor
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    • "However, there is a general agreement among those who have investigated this area that a large percentage of the human population has HSV-1 DNA in the CNS. During the course of the AD, protein 'plaques' and 'tangles' develop in the structure of the brain, leading to the death of brain cells [100] [101] [102] [103] [104] [105] [106] [107] [108] [109] [110] [111] [112] [113] [114] [115] [116] [117] [118] [119] [120]. "
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    ABSTRACT: Neurodegenerative and neurobehavioral diseases are caused by chronic and neuropathic virus infection resulting in loss of neurons and axons in the central nervous system at old age. There exists co-evidence of systemic viral infection with some neurodegenerative conditions like Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, autism spectrum disorders, HIV associated neurocognitive disorders. With increase in lifespan the incidence of neurodegenerative diseases are simultaneously increasing affecting around 37 million people worldwide, and are important cause of mortality. In addition to established non-viral-induced reasons for neurodegenerative diseases, neuropathic infections and virus associated neurodegenerative diseases have also been proposed. The neuronal degeneration can be affected by virus infection in both direct and indirect ways. Viruses attack human immune system, can affect nervous system along with tampering with the classical pathways of neurodegenerative diseases. Viruses can enter the central nervous system, but the exact mechanism is not understood well. Various studies have supported the viruses and non-virus mediated neurodegeneration at the cellular, molecular, genomic and proteomic levels. The main focus of this review is to show the association of virus infections in neurodegenerative and neurobehavioral diseases, so that the possible mechanism and pathway of neurodegenerative diseases could be explained. This information will further strengthen the new concept and ideas for neurodegenerative and neurobehavioral diseases treatment.
    CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) 09/2014; DOI:10.2174/1871527313666140917122402 · 2.63 Impact Factor
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    • "In contrast to the high frequency of HSV1 DNA in elderly brains, the viral DNA was found to be present in only a very small proportion of brains of young people and children (Wozniak et al., 2005, 2009). It was therefore suggested that HSV1 enters the brain in older age, as a consequence of the decline in the immune system with age. "
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    ABSTRACT: Abstract HSV1, when present in brain of carriers of the type 4 allele of the apolipoprotein E gene (APOE), has been implicated as a major factor in AD. It is proposed that virus is normally latent in many elderly brains but reactivates periodically (as in the peripheral nervous system) under certain conditions, for example stress, immunosuppression, and peripheral infection, causing cumulative damage and eventually development of AD. Diverse approaches have provided data that explicitly support, directly or indirectly, these concepts. Several have confirmed HSV1 DNA presence in human brains, and the HSV1-APOE-ε4 association in AD. Further, studies on HSV1-infected APOE-transgenic mice have shown that APOE-e4 animals display a greater potential for viral damage. Reactivated HSV1 can cause direct and inflammatory damage, probably involving increased formation of beta amyloid (Aβ) and of AD-like tau (P-tau) - changes found to occur in HSV1-infected cell cultures. Implicating HSV1 further in AD is the discovery that HSV1 DNA is specifically localised in amyloid plaques in AD. Other relevant, harmful effects of infection include the following: dynamic interactions between HSV1 and amyloid precursor protein (APP), which would affect both viral and APP transport; induction of toll-like receptors in HSV1-infected astrocyte cultures, which has been linked to the likely effects of reactivation of the virus in brain. Several epidemiological studies have shown, using serological data, an association between systemic infections and cognitive decline, with HSV1 particularly implicated. Genetic studies too have linked various pathways in AD with those occurring on HSV1 infection. In relation to the potential usage of antivirals to treat AD patients, acyclovir (ACV) is effective in reducing HSV1-induced AD-like changes in cell cultures, and valacyclovir, the bioactive form of ACV, might be most effective if combined with an antiviral that acts by a different mechanism, such as
    Frontiers in Aging Neuroscience 08/2014; 6:202. DOI:10.3389/fnagi.2014.00202 · 4.00 Impact Factor
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Marc Combrinck