Miller RM, Federoff HJ.
Isoform-specific effects of ApoE on HSV immediate early gene expression and establishment of latency.
Neurobiol Aging. 2008 Jan;29(1):71-7.
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In this innovative study, Miller and Federoff report new evidence intimately linking apolipoprotein E (ApoE) and herpes simplex virus type 1 (HSV1), which strengthens the case that the two factors together are important in Alzheimer disease (AD).
The authors investigated the effect of ApoE on the expression of specific genes during the two types of infection that HSV1 can cause: acute and latent. In the former, viral gene expression occurs, the virus replicates, and whole virus particles are produced which spread from cell to cell, eventually causing cell death. The authors studied the so-called immediate early (IE) genes. During latency, gene expression is limited to the latency-associated transcripts (LAT), which were studied by the authors; no viruses are produced, and no obvious ill effects occur in the host cell (thus ensuring host survival and thereby that of the virus).
In humans, latent HSV1 resides lifelong in the trigeminal ganglia of some 80-90 percent of people, but it can reactivate during stress or immunosuppression, leading to productive infection. This process occurs repeatedly, with ApoE4 carriers being particularly susceptible to overt reactivation, i.e., cold sores [1,2]. Many elderly people harbor latent HSV1 in brain, too , and they have a greater risk of developing AD if they carry an ApoE4 allele [1,2]. The ways in which HSV1 and ApoE interact are unclear, and it is imperative to determine their interaction for elucidating the development of AD.
Miller and Federoff used primary neuronal cultures from ApoE-transgenic and ApoE-knockout mice to assess viral IE gene expression, and found the highest level in cells from KO and ApoE4 mice. Examination of the Tgs showed that LAT expression was least in KO and ApoE4 animals. The authors conclude that in the latter, the virus remains longer than the usual 5 or so days in the replicative phase prior to latency, thus prolonging lytic infection and cell death, and that the data support the concept that HSV1 in brain and ApoE4 synergistically promote neuronal death—death occurring in AD. Interestingly, a study by Hill et al.  showed similarly the importance of ApoE in the response to HSV1, latency being less efficiently established in the trigeminal ganglia of ApoE KO mice than in control animals. The Miller-Federoff data are consistent also, as the authors point out, with those of Perng et al. , indicating that LAT expression in vitro blocks apoptotic death induced by various insults.
Two major questions remain:
1. What is the critical damage relevant to AD caused by HSV1 and ApoE4? Miller and Federoff suggest that the greater vulnerability of infected neurons in E4 carriers leads to Aβ-mediated synaptic and cellular dysfunction. Our current studies (submitted) show a direct effect of HSV1 on amyloid aggregation and on abnormal phosphorylation of tau, either of which could cause such damage. Possibly, both indirect and direct effects of HSV1 are relevant to AD.
2. How do HSV1 and ApoE interact? Miller and Federoff suggest that as viral load was independent of ApoE in their neuronal cultures, isoform-specific damage occurs after virus entry into cells. However, in the sole other study of HSV1-infected ApoE-transgenic mice, by Burgos et al. , viral load in brain was highest in ApoE4 animals. Possibly, the different routes of injection and different tissues account for this. From our cell studies, we have invoked another mechanism: that virus and protein compete for common receptors in the cell surface, the isoform with the weakest binding—in this case ApoE4—allowing greater viral entry, spread, and damage. This idea is supported by investigations of selected infectious diseases  in which the micro-organism binds to an ApoE receptor; these show that ApoE indeed influences severity of disease. Clearly, the answers must await further work by the authors—which we look forward to very keenly—especially on the CNS of their animals.
Finally, this study on HSV1 and the influence of ApoE on outcome of infection is most welcome. There is a paucity of publications owing to lack of funding and an inexplicable prejudice against a role for micro-organisms in AD. It is gratifying that similar “heresies” in the past, relating micro-organisms to certain cancers and to stomach ulcers, were eventually proved correct.
Itzhaki RF, Lin WR, Shang D, Wilcock GK, Faragher B, Jamieson GA.
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Bhattacharjee PS, Neumann DM, Stark D, Thompson HW, Hill JM.
Apolipoprotein E modulates establishment of HSV-1 latency and survival in a mouse ocular model.
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Perng GC, Jones C, Ciacci-Zanella J, Stone M, Henderson G, Yukht A, Slanina SM, Hofman FM, Ghiasi H, Nesburn AB, Wechsler SL.
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Burgos JS, Ramirez C, Sastre I, Bullido MJ, Valdivieso F.
ApoE4 is more efficient than E3 in brain access by herpes simplex virus type 1.
Neuroreport. 2003 Oct 6;14(14):1825-7.
Itzhaki RF, Wozniak MA.
Herpes simplex virus type 1, apolipoprotein E, and cholesterol: a dangerous liaison in Alzheimer's disease and other disorders.
Prog Lipid Res. 2006 Jan;45(1):73-90.
The role of infectious disease, and particularly the common neurotrophic virus herpes simplex type 1 (HSV-1), in Alzheimer disease (AD) has been relatively neglected. The case for a role of HSV-1 is growing stronger with this report by Miller and Federoff.
HSV-1 is the cause of the common cold sore, and predicted to infect 85 percent of Americans. After infecting the cell of the lip, HSV secondarily enters the sensory processes of neurons and travels within them to the trigeminal ganglion, where it either enters latency or replicates. From the bipolar neurons in the trigeminal ganglion, HSV has a straight shot to the brainstem, and from there it's only a hop, skip, and a jump to the cortex or hippocampus of the brain.
HSV virions are associated with high levels of the amyloid precursor protein (APP; see Satpute-Krishnan et al., 2003), which produces the toxic peptide fragments present in senile plaques. We found recently that APP is sufficient to hitch viral-sized particles to neuronal transport machinery (Satpute-Krishnan et al., 2006). Thus cellular APP could hitch invading HSV virions to neuronal motors and redistribute the virus throughout the brain.
Other evidence also supports a link between AD and HSV. HSV genomic DNA is found in human brains in areas affected by AD (Jamieson et al., 1991 and 1992), and there is an epidemiological correlation between AD with the ApoE4 allele and HSV (Itzhaki et al., 2001). Hence HSV-1 could play a role in risk or progression of AD.
In the Miller and Federoff paper, a set of transgenic mice carrying either no ApoE gene or one or the other of the three major human alleles were tested for viral behavior. Significantly, mice with the ApoE4 allele expressed higher levels of the viral early genes and less of the latency gene. If this also occurs in humans carrying the ApoE4 allele, they would have more frequent reactivations of the virus with more virus emerging from latently infected cells in the brain over time. Such chronic viral emergence over time could cause loss of neurons as that seen in AD. The documented physical association of virus with APP and with ApoE would result in mislocalization of these proteins within the brain and thereby possibly induce abnormal proteolysis and plaque formation.
Since HSV replication can be suppressed with anti-viral therapy, these separate and supportive results from three different labs—the Federoff, Itzhaki, and Bearer labs—suggest an infectious mechanism for AD progression.
Satpute-Krishnan P, DeGiorgis JA, Bearer EL.
Fast anterograde transport of herpes simplex virus: role for the amyloid precursor protein of alzheimer's disease.
Aging Cell. 2003 Dec;2(6):305-18.
Satpute-Krishnan P, DeGiorgis JA, Conley MP, Jang M, Bearer EL.
A peptide zipcode sufficient for anterograde transport within amyloid precursor protein.
Proc Natl Acad Sci U S A. 2006 Oct 31;103(44):16532-7.
Jamieson GA, Maitland NJ, Wilcock GK, Yates CM, Itzhaki RF.
Herpes simplex virus type 1 DNA is present in specific regions of brain from aged people with and without senile dementia of the Alzheimer type.
J Pathol. 1992 Aug;167(4):365-8.
Itzhaki RF, Dobson CB, Lin WR, Wozniak MA.
Association of HSV1 and apolipoprotein E-varepsilon4 in Alzheimer's disease.
J Neurovirol. 2001 Dec;7(6):570-1.
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