Frequent Release of Low Amounts of Herpes Simplex Virus from Neurons: Results of a Mathematical Model

Department of Medicine, University of Washington, Seattle, WA 98195, USA.
Science translational medicine (Impact Factor: 15.84). 11/2009; 1(7):7ra16. DOI: 10.1126/scitranslmed.3000193
Source: PubMed


Herpes simplex virus-2 (HSV-2) is a sexually transmitted infection that is the leading cause of genital ulcers worldwide. Infection is life long and is characterized by repeated asymptomatic and symptomatic shedding episodes of virus that are initiated when virus is released from neurons into the genital tract. The pattern of HSV-2 release from neurons into the genital tract is poorly understood. We fit a mathematical model of HSV-2 pathogenesis to curves generated from daily quantification of HSV in mucosal swabs performed from patients with herpetic genital ulcers. We used virologic parameters derived from model fitting for stochastic model simulations. These simulations reproduced previously documented estimates for shedding frequency, and herpetic lesion diameter and frequency. The most realistic model output occurred when we assumed minimal amounts of daily neuronal virus introduction. In our simulations, small changes in average total quantity of HSV-2 released from neurons influenced detectable shedding frequency, while changes in frequency of neuronal HSV-2 release had little effect. Frequent HSV-2 shedding episodes in humans are explained by nearly constant release of small numbers of viruses from neurons that terminate in the genital tract.

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Available from: Joshua Schiffer, Oct 03, 2015
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    • "Reactivation is normally associated with stress factors such as hormonal alterations, ultraviolet light exposure, and immunosuppression [9,10]. However, a study using mathematical models of HSV-2 (which is closely related to HSV-1) reactivation revealed that the virus is constantly released from neurons in small amounts, thereby activating the immune system, which in turn inhibits viral replication and promotes a balance that prevents the clinical reactivation of the disease [11]. "
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    ABSTRACT: Herpes simplex 1 (HSV-1) causes various human clinical manifestations, ranging from simple cold sores to encephalitis. Innate immune cells recognize pathogens through Toll-like receptors (TLRs), thus initiating the immune response. Previously, we demonstrated that the immune response against HSV-1 is dependent on TLR2 and TLR9 expression and on IFN gamma production in the trigeminal ganglia (TG) of infected mice. In this work, we further investigated the cells, molecules, and mechanisms of HSV-1 infection control, especially those that are TLR-dependent. C57BL/6 wild-type (WT), TLR2-/-, TLR9-/-, and TLR2/9-/- mice were intranasally infected with HSV-1. On the viral peak day, the TG and brains were collected from mice and TLR expression was measured in the TG and brain and inducible nitric oxide synthase (iNOS) expression was measured in the TG by real-time PCR. Immunofluorescence assays were performed in mice TG to detect iNOS production by F4/80+ cells. Intraperitoneal macrophages nitric oxide (NO) production was evaluated by the Griess assay. WT, CD8-/-, RAG-/-, and iNOS-/- mice were intranasally infected in a survival assay, and their cytokine expression was measured in the TG by real-time PCR. Infected WT mice exhibited significantly increased TLR expression, compared with their respective controls, in the TG but not in the brain. TLR-deficient mice had moderately increased TLR expression in the TG and brain in compare with the non-infected animals. iNOS expression in the WT infected mice TG was higher than in the other groups with increased production by macrophages in the WT infected mice, which did not occur in the TLR2/9-/- mice. Additionally, the intraperitoneal macrophages of the WT mice had a higher production of NO compared with those of the TLR-deficient mice. The CD8-/-, RAG-/-, and iNOS-/- mice had 100% mortality after the HSV-1 infection compared with 10% of the WT mice. Cytokines were overexpressed in the iNOS-/- infected mice, while the RAG-/- mice were nearly unresponsive to the virus. TLRs efficiently orchestrate the innate immune cells, eliciting macrophage response (with NO production by the macrophages), thereby controlling the HSV-1 infection through the immune response in the TG of mice.
    Journal of Neuroinflammation 01/2014; 11(1):20. DOI:10.1186/1742-2094-11-20 · 5.41 Impact Factor
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    • "The median duration and peak viral production of the 24 ulcers were 2.5 days (range: 0.6–4.6 days) and 5.2 log 10 HSV DNA copies (range: 2.0–8.0 log 10 ), respectively. We calculated diameter of each ulcer during simulations based on the number of missing cells due to death from infection, and defined a lesion as any episode with a >1 mm ulcer (Schiffer et al., 2009 "
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    ABSTRACT: Herpes simplex virus-2 (HSV-2) is shed episodically, leading to occasional genital ulcers and efficient transmission. The biology explaining highly variable shedding patterns, in an infected person over time, is poorly understood. We sampled the genital tract for HSV DNA at several time intervals and concurrently at multiple sites, and derived a spatial mathematical model to characterize dynamics of HSV-2 reactivation. The model reproduced heterogeneity in shedding episode duration and viral production, and predicted rapid early viral expansion, rapid late decay, and wide spatial dispersion of HSV replication during episodes. In simulations, HSV-2 spread locally within single ulcers to thousands of epithelial cells in <12 hr, but host immune responses eliminated infected cells in <24 hr; secondary ulcers formed following spatial propagation of cell-free HSV-2, allowing for episode prolongation. We conclude that HSV-2 infection is characterized by extremely rapid virological growth and containment at multiple contemporaneous sites within genital epithelium. DOI:
    eLife Sciences 04/2013; 2(2):e00288. DOI:10.7554/eLife.00288 · 9.32 Impact Factor
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    • "Studies of mutations that affect individual miRNAs should help address this possibility. A final consideration is that in humans, unlike in mice, spontaneous reactivation of HSV is frequent (Margolis et al., 2007; Mark et al., 2008; Schiffer et al., 2009). It is possible that interference with LAT functions, including miRNAs (e.g. by oligonucleotides that antagonize miRNAs), could have a greater effect in humans, and thus disrupt latency. "
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    ABSTRACT: Several herpes simplex virus 1 microRNAs are encoded within or near the latency associated transcript (LAT) locus, and are expressed abundantly during latency. Some of these microRNAs can repress the expression of important viral proteins and are hypothesized to play important roles in establishing and/or maintaining latent infections. We found that in lytically infected cells and in acutely infected mouse ganglia, expression of LAT-encoded microRNAs was weak and unaffected by a deletion that includes the LAT promoter. In mouse ganglia latently infected with wild type virus, the microRNAs accumulated to high levels, but deletions of the LAT promoter markedly reduced expression of LAT-encoded microRNAs and also miR-H6, which is encoded upstream of LAT and can repress expression of ICP4. Because these LAT deletion mutants establish and maintain latent infections, these microRNAs are not essential for latency, at least in mouse trigeminal ganglia, but may help promote it.
    Virology 07/2011; 417(2):239-47. DOI:10.1016/j.virol.2011.06.027 · 3.32 Impact Factor
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