Article

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: 2.22). 02/2005; 75(2):300-6. DOI: 10.1002/jmv.20271
Source: PubMed

ABSTRACT 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.

1 Follower
 · 
155 Views
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    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 · 2.70 Impact Factor
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Diabetes mellitus type 2 is a metabolic disorder characterized by high blood glucose due to insulin deficiency or resistance. Alzheimer's disease (AD) is a complex neurodegenerative disease leading to irreversible loss of neurons, intellectual abilities, memory and reasoning. The worldwide prevalence of diabetes and AD in elderly population is a major public health concern. Interestingly, both health issues are unraveling the puzzling links. The clinico-pathological relationship between diabetes and AD has been reported at genomic and proteomic levels. The association of virus infection in type 2 diabetes mellitus and AD has been reported in few recent studies, some have shown direct evidence of virus infection in diabetes and AD while other have shown that diabetes increases the risk of developing AD. This review aims to summarize the association of few common viruses like Hepatitis C Virus and Herpes Simplex Virus-1 which affects both these two age-related devastating diseases. We also discuss the pathological links of Influenza virus, Cytomegalovirus, West Nile virus, Enterovirus, Herpes Simplex Virus-2, Hepatitis viruses in diabetes and Influenza virus, Picornavirus and Borna disease virus in AD. Establishing such relationships and defining their common pathogenesis and patho-physiological mechanisms may lead to new concepts and paths for developing novel preventive strategies and pharmacological treatment options for diabetes and AD. This study may aid in future for the identification of a single or a panel of likely blood-based viral biomarkers for early diagnosis of diabetes and AD with high sensitivity and specificity.
    CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) 05/2014; 13(3). DOI:10.2174/18715273113126660164 · 2.70 Impact Factor
  • Source
    • "Since then a growing body of evidence has accumulated suggesting a link between HSV-1 infection and AD. Among these are relevant studies showing the presence of HSV-1 in the brains of patients carrying the type 4 allele of the apolipoprotein E gene (APOE), a well-known susceptibility factor for AD [7] [8] and of anti-HSV IgG antibodies in cerebrospinal fluid (CSF) of adult and AD patients, but not in children younger than 7 years old, suggesting that the virus can reach the brain during adulthood perhaps favored by a decline in the immune system [9]. In agreement with this view, a recent study reported an increased risk of AD in a large population-based prospective study in elderly subjects with a positive detection of anti- HSV (HSV-1 and HSV-2) IgM antibodies [10]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: Currently, it is unclear whether asymptomatic recurrent reactivations of herpes simplex virus type 1 (HSV-1) occur in the central nervous systems of 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 neuropathies associated with chronic neuroinflammation. Objective: The aim of this study was to assess in vivo inflammatory and neurodegenerative markers in the brain during productive and latent HSV-1 infection using a mouse model of herpes simplex encephalitis. Methods: Neuroinflammation and neurodegeneration markers were evaluated in mice trigeminal ganglia and cerebral cortex during HSV-1 infection, by immunohistochemistry, western blot, and RT-PCR. Results: Neuronal ICP4 viral antigen expression indicative of a reactivation episode during asymptomatic latency of HSV-1 infection in mice was accompanied by upregulation of neuroinflammatory (toll-like receptor-4, interferon α/β, and p-IRF3) and early neurodegenerative markers (phospho-tau and TauC3). Conclusions: HSV-1 reactivation from latency induced neuroinflammatory and neurodegenerative markers in the brain of asymptomatic mice suggesting that recurrent reactivations could be associated with cumulative neuronal dysfunctions.
    Journal of Alzheimer's disease: JAD 12/2013; 39(4). DOI:10.3233/JAD-131706 · 4.15 Impact Factor
Show more

Marc Combrinck