Effect of Apolipoprotein E on the Cerebral Load of Latent Herpes Simplex Virus Type 1 DNA

Lab CX340, Centro de Biología Molecular, Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain.
Journal of Virology (Impact Factor: 4.44). 07/2006; 80(11):5383-7. DOI: 10.1128/JVI.00006-06
Source: PubMed


Herpes simplex virus type 1 (HSV-1) is neurotropic and enters a latent state lasting the lifetime of the host. This pathogen has recently been proposed as a risk factor for Alzheimer's disease (AD) in conjunction with apolipoprotein E4 (ApoE4). In a murine acute infection model, we showed that viral neuroinvasiveness depends directly on the overall ApoE dosage and especially on the presence of isoform ApoE4. If an interaction between ApoE and HSV-1 is involved in AD, it may occur during latency rather than during acute infection. Certainly, ApoE plays an important role in late-onset AD, i.e., at a time in life when the majority of people harbor HSV-1 in their nervous system. In the present work, wild-type, APOE knockout, APOE3, and APOE4 transgenic mice were used to analyze the influence of the ApoE profile on the levels of latent virus DNA. The knockout mice had significantly lower concentrations of the virus in the nervous system than the wild-type mice, while the APOE4 mice had very high levels in the brain compared to the APOE3 animals. ApoE4 seems to facilitate HSV-1 latency in the brain much more so than ApoE3. The APOE dosage correlated directly with the HSV-1 DNA concentration in the brain, strengthening the hypothesis that HSV-1, together with ApoE, might be involved in AD.

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    • "The interaction of aging, HSV1 infection, gender and APOE in mouse brains was investigated by Guzman-Sanchez et al. (2012), who infected 2 month-old male and female wild-type and APOE-knock-out mice, and studied them over the following 16 months. Previous work by the same group (Burgos et al., 2003, 2006), had shown that APOE determines the viral load in the CNS during the acute and latent phases of infection, and was greater in APOE-ε4-transgenic than in APOE-e3 animals; also the load in female brains was greater than in males. Their 2012 study found that the viral load in brain was maximal during the acute phase, declined during adulthood and then increased with ageing, and that in wild-type female mice the load was 43 times greater than in apoE-K/O animals. "
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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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    • "May 2014 | Volume 5 | Article 97 | 3 with HSV-1, ApoE4 was more efficient than ApoE3 in promoting viral colonization of the brain (Burgos et al., 2006b). However, many genes and proteins implicated in AD, other than ApoE, have been found to interact with herpes simplex viral genome or regulate its life cycle, further supporting the hypothesized synergy between host and pathogens in causing AD-like brain damage (Carter, 2008). "
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    ABSTRACT: Among the multiple factors concurring to Alzheimer's disease (AD) pathogenesis, greater attention should be devoted to the role played by infectious agents. Growing epidemiological and experimental evidence suggests that recurrent herpes simplex virus type-1 (HSV-1) infection is a risk factor for AD although the underlying molecular and functional mechanisms have not been fully elucidated yet. Here, we review literature suggesting the involvement of HSV-1 infection in AD also briefly mentioning possible pharmacological implications of these findings.
    Frontiers in Pharmacology 05/2014; 5:97. DOI:10.3389/fphar.2014.00097 · 3.80 Impact Factor
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    • "[2], [3] Animal studies in mice have shown that HSV-1 disease severity relies on three factors; innate host resistance, host immune response and viral strains. [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], Neurovirulence studies with different viral strains in infected mice show that disease severity varies from no disease to lethal encephalitis. [18], [19] Further phylogenetic and genomic analysis of viral strains may aid in understanding the genetic aspects virulence. "
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    ABSTRACT: We compared 31 complete and nearly complete globally derived HSV-1 genomic sequences using HSV-2 HG52 as an outgroup to investigate their phylogenetic relationships and look for evidence of recombination. The sequences were retrieved from NCBI and were then aligned using Clustal W. The generation of a maximum likelihood tree resulted in a six clade structure that corresponded with the timing and routes of past human migration. The East African derived viruses contained the greatest amount of genetic diversity and formed four of the six clades. The East Asian and European/North American derived viruses formed separate clades. HSV-1 strains E07, E22 and E03 were highly divergent and may each represent an individual clade. Possible recombination was analyzed by partitioning the alignment into 5 kb segments, performing individual phylogenetic analysis on each partition and generating a.phylogenetic network from the results. However most evidence for recombination spread at the base of the tree suggesting that recombination did not significantly disrupt the clade structure. Examination of previous estimates of HSV-1 mutation rates in conjunction with the phylogenetic data presented here, suggests that the substitution rate for HSV-1 is approximately 1.38×10(-7) subs/site/year. In conclusion, this study expands the previously described HSV-1 three clade phylogenetic structures to a minimum of six and shows that the clade structure also mirrors global human migrations. Given that HSV-1 has co-evolved with its host, sequencing HSV-1 isolated from various populations could serve as a surrogate biomarker to study human population structure and migration patterns.
    PLoS ONE 10/2013; 8(10):e76267. DOI:10.1371/journal.pone.0076267 · 3.23 Impact Factor
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