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Ocular HSV: Mechanism of virus reactivation

眼部 HSV：病毒再激活机制

基本信息

批准号：
10165727
负责人：
HOMAYON GHIASI
金额：
$ 41.23万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10165727
关键词：
Afferent Neurons Apoptosis Back Baculoviruses Binding Blindness CD8-Positive T-Lymphocytes Cells Characteristics Clinical Computer Models Data Development Engineering Eye Eye Infections Eye diseases Failure Frequencies Gene Proteins Genes Glycoproteins Goals Herpesviridae Herpesvirus 1 Herpetic Keratitis Human Immune Evasion Immune response Individual Infection Knowledge Maintenance Maps Mediator of activation protein Messenger RNA Modeling Molecular Target Mus Mutate Neurons Oryctolagus cuniculus PVRL1 Peripheral Phase Plasmids Play Positioning Attribute Primary Infection Process Production Promoter Regions Proteins Publishing RNA Recombinants Recurrence Recurrent disease Regulation Role Signal Transduction Simplexvirus Structure of trigeminal ganglion System T cell regulation T cell response T-Lymphocyte Testing Transfection Travel Untranslated RNA Up-Regulation Validation Viral Viral Genes Viral Genome Viral Proteins Virus Virus Activation Virus Diseases Virus Latency Virus Receptors Wild Type Mouse acute infection base clinically relevant clinically significant exhaustion in vivo inhibitor-of-apoptosis protein innovation latency associated transcript mouse model nectin novel prevent programmed cell death protein 1 promoter reactivation from latency receptor recombinant virus response simplexvirus receptor stable cell line

项目摘要

Project Summary Following primary ocular HSV-1 infection, the virus replicates in the eye and establishes latency in the trigeminal ganglia (TG). In a latently infected individual, the virus can occasionally reactivate and travel back to the eye causing recurrent disease. Reactivation from latency is the major cause of eye disease. However, the mechanisms underlying this process are not well defined, and currently it is not clear whether reactivation reflects a failure in latency mechanisms or independent mechanisms that break latency. It is well established that the continued expression of the HSV-1 Latency Associated Transcript (LAT) is a characteristic of latency, and this is associated with suppression of apoptosis and regulation of T cell responses to the infected sensory neurons. Recently, we found that in the TG of mice infected with LAT(-) virus, the levels of the HSV-1 receptor, HVEM, but not other HSV-1 receptors was significantly down-regulated. Furthermore, HSV-1 latency and reactivation were reduced significantly in HVEM-/- mice as compared to wild-type mice. Notably, the LAT function in upregulating HVEM mapped to two recently described small non-coding LAT RNAs (sncRNA1 and 2), since HVEM was upregulated following transient transfection with plasmids expressing either small non- coding RNA. In parallel, we have found that viral glycoprotein gD, capable of binding HVEM and triggering its signaling through NF-κB, is expressed at low levels in latently infected TG. Collectively, our preliminary data provide compelling evidence supporting the hypothesis that LAT can enhance latency-reactivation and T-cell exhaustion by upregulating HVEM, which in turn promotes HSV-1 reactivation, possibly by facilitating the binding of gD to HVEM. Although the LAT(-) virus expressing baculovirus inhibitor of apoptosis protein gene (cpIAP) had similar levels of latency as wild-type LAT(+) virus, this recombinant virus did not increase HVEM levels suggesting that this reactivation mechanism does not promote reactivation by regulating responsiveness to apoptosis. Rather, this mechanism appears to interfere with the ability of LAT to promote immune evasion. We propose to test this hypothesis using in vivo analyses of engineered recombinant viruses to: (1) Test whether binding of HSV-1 gD to HVEM is required for efficient reactivation in TG of latently infected mice; and (2) Test whether the LAT sncRNAs upregulate HVEM by binding to the HVEM promoter. Validation of this hypothetical model will identify previously undescribed mechanisms that contribute to HSV-1 reactivation and will provide the framework for identification of molecular targets and viral immune evasion response that could be exploited to better manage latent HSV infection. CLINICAL SIGNIFICANCE AND

项目总结