Apolipoprotein E Modulates Establishment of HSV-1 Latency and Survival in a Mouse Ocular Model

Louisiana State University Health Sciences Center New Orleans, New Orleans, Louisiana, United States
Current Eye Research (Impact Factor: 1.64). 10/2006; 31(9):703-8. DOI: 10.1080/02713680600864600
Source: PubMed


To evaluate and compare the neuroinvasiveness and neurovirulence after ocular HSV-1 infection in ApoE knockout (ApoE-/-) and control C57BL/6 (ApoE+/+) mice.
Age-matched (14 weeks of age) C57BL/6J (ApoE+/+) female mice and female ApoE knockout (ApoE-/-) mice were inoculated by corneal scarification with HSV-1 strain 17Syn+. Analysis of HSV-1 replication in the mouse cornea was assessed through infectious virus assays of ocular (tear film) swabs at 1 to 5 days postinoculation (PI), slit-lamp examination (SLE) of corneas at PI days 1 to 7, and survival of infected mice. The contribution of apoE to the efficient establishment of latency was measured by real-time PCR quantitation of the latent viral genome in the trigeminal ganglia (TG) of infected mice.
These studies showed that HSV-1 strain 17Syn+ replicates efficiently in the eyes, regardless of the host ApoE genotype. Neither the scoring of corneal pathology via SLE nor the infectious virus assay of the tear film resulted in any statistical differences between ApoE knockout (-/-) mice or the C57BL/6 (ApoE+/+) mice. In mice latently infected with HSV-1, our real-time PCR data showed significantly lower viral copy numbers of HSV-1 DNA in ApoE knockout (ApoE-/-) mice compared with C57BL/6 (ApoE+/+) mice. C57BL/6 (ApoE+/+) mice are more susceptible to the neurovirulence of HSV-1 strain 17Syn+ than female ApoE knockout (-/-) mice, as demonstrated by the fact that 50% (7/14) of the female C57BL/6 (ApoE+/+) mice inoculated with 17Syn+ died, as opposed to none (0/14) of the age- and sex-matched ApoE knockout mice.
These data indicate that age (14 weeks) and sex-matched (female) wild mice with an ApoE null background (ApoE-/-) are more resistant and less efficient in the establishment of latency compared with ApoE+/+ mice in the C57BL/6 background.

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    • "Although we did not include apoE null (−/−) mice in our current study, using a similar mouse ocular model, we have reported that murine apoE has no role in ocular viral shedding and acute corneal pathology (Bhattacharjee et al., 2006 "
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    ABSTRACT: The isoform-specific role of human apolipoprotein E (apoE) has been assessed in a mouse model of ocular herpes. Female, age-matched transgenic mice knocked-in for the human allele apoE3 or apoE4 and their parent C57Bl/6 mice were inoculated corneally with HSV-1 strain KOS. Ocular HSV-1 pathogenesis was monitored through viral replication and clinical progression of stromal opacity and neovascularization by slit-lamp examination. Establishment of latency was determined by analysis of HSV-1 DNA (copy number) by specific real-time PCR in the cornea, trigeminal ganglia (TG), and brain. Representative groups of transgenic mice were sacrificed for the analysis of gene expression of vascular endothelial growth factor (VEGF) by reverse-transcription PCR, and apoE expression by Western blot analysis. At 6days post-infection (P.I.), the ocular infectious HSV-1 titer was significantly higher (p<0.05) in apoE4 mice compared with apoE3 and C57Bl/6 mice. Corneal neovascularization in apoE4 mice was significantly higher (p<0.05) than apoE3 and C57Bl/6 mice. The onset of corneal opacity in apoE4 mice was accelerated during days 9-11 P.I.; however, no significant difference in severity was seen on P.I. days 15 and beyond. At 28 days P.I., infected mice of all genotypes had no significant differences in copy numbers (range 0-15) of HSV-1 DNA in their corneas, indicating that HSV-1 DNA copy numbers in cornea are independent of apoE isoform regulation. At 28 days P.I., both apoE4 and C57Bl/6 mice had a significantly higher (p=0.001) number of copies of HSV-1 DNA in TG compared with apoE3. ApoE4 mice also had significantly higher (p=0.001) copies of HSV-1 DNA in their TGs compared with C57Bl/6 mice. In brain, both apoE4 and C57Bl/6 mice had significantly higher numbers (p<or=0.03) of copies of HSV-1 DNA compared with apoE3 mice. However, the number of HSV-1 DNA copies in the brain of C57Bl/6 mice was not significantly different than that of apoE4 (p=0.1). Comparative molecular analysis between apoE3 and apoE4 mice on selected days between 7 and 28 P.I., inclusive, revealed that the corneas of apoE4 mice expressed VEGF. None of the corneas in the apoE3 mice expressed VEGF during this time. Western blot analysis showed proteolytic cleavage of the apoE protein in the corneas of the apoE4 mice. Through days 14-28 P.I., a approximately 29 kDa C-terminal truncated apoE fragment was present in the corneas of apoE4 mice, but not in apoE3 mice. ApoE4 is a risk factor for ocular herpes, in part, through increased replication of virus in the eye, an earlier onset in clinical opacity, significantly higher neovascularization, and increased HSV-1 DNA load in TG and brain than that of apoE3. Increased pathogenesis of ocular herpes in apoE4 mice was also mediated, in part through up-regulated expression of VEGF and apoE proteolysis in the cornea. This is the first report linking a human gene, apoE4, as a risk factor for ocular herpes pathogenesis in a transgenic mouse model.
    Experimental Eye Research 06/2008; 87(2):122-30. DOI:10.1016/j.exer.2008.05.007 · 2.71 Impact Factor
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    • "The authors conclude that in the latter two groups, the virus remains longer than the usual five 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 APOE- ε4 synergistically promote neuronal death – death occurring in AD. Interestingly, a study by Bhattacharjee et al. similarly showed 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 [10]. The Miller-Federoff data are also consistent, as the authors point out, with those of Perng et al. indicating that LAT expression in vitro blocks apoptotic death induced by various insults [68]. "
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    ABSTRACT: Alzheimer's disease is a modern scourge and is likely to become increasingly so in the future, with increasing longevity. The disease has been investigated for over one hundred years yet its causes and that of the neuropathological characteristics seen in AD brain are still completely unknown. Evidence for a major causative role of a common virus, herpes simplex virus type 1 (HSV1), acting in combination with a genetic factor - the type 4 allele of the apolipoprotein gene, a known susceptibility factor - is presented here. The characteristics of the virus, some of which make it an especially likely candidate for this role, are described, as are the many precedents for the action of a genetic factor modulating outcome of infection. Various possible ways in which HSV1 might lead to development of AD, such as its up-regulation of various enzymes and in particular certain kinases, its effect on the cell cycle, on autophagy, and its inflammatory and oxidative effects are also discussed. It is concluded that there is strong evidence that the virus is indeed a major factor in AD and therefore there is a strong case for appropriate treatment, and possibly for prevention in the future.
    Journal of Alzheimer's disease: JAD 06/2008; 13(4):393-405. · 4.15 Impact Factor
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    • "Specifically, the mouse brains of ApoE ε 4 mice had significantly higher loads of HSV-1 than the ApoE ε 3 in all four brain regions (mid-brain, ventricles, cortex, and cerebellum). This report supplies direct evidence that the human ε 4 increases the susceptibility, severity, and neuroinvasiveness of HSV-1 compared to mice possessing human allele ε 3. Based on recent results reported (Bhattacharjee et al., 2006) from our lab and our understanding of the current concepts of ocular HSV-1 neurovirology, we have hypothesized, in Figs. 1 and 2, the pathogenesis of acute infection, development of latency, and neuronal reactivation based on ApoE genotypes. "
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    ABSTRACT: Apolipoprotein E (ApoE) alleles have been reported to affect the clinical outcome of numerous cardiovascular, neurodegenerative, and viral infectious diseases, including atherosclerosis, Alzheimer's disease (AD), hepatitis C, and HIV. The major alleles of ApoE are 2, 3, and 4. ApoE genotypes have been hypothesized to regulate many biological functions, resulting in significant changes in the onset and/or outcome (severity and duration) of several clinical conditions. Based on genetic analyses in human and animal studies using knockout (ApoE -/-) mice and mice transgenic for human 3 and 4, we present evidence that strongly suggests that the ApoE alleles can regulate the pathogenesis of ocular herpes simplex virus type 1 (HSV-1) infections. This review will summarize the major studies that support this hypothesis. Significant gender based differences in HSV-1 pathogenesis have also been reported, suggesting that hormonal regulation combined with ApoE genotype plays a significant role in HSV-1 pathogenesis. Identification of specific mechanisms in ocular HSV-1 infections related to the ApoE alleles and gender could lead to therapeutic intervention based on the properties of the apoE isoforms. While many clinical investigations have been reported and, to a lesser extent, transgenic mouse studies have been conducted, no specific mechanisms of how ApoE induces or alters clinical disease are known.
    Experimental Eye Research 06/2007; 84(5):801-11. DOI:10.1016/j.exer.2006.08.001 · 2.71 Impact Factor
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