Therapeutic immunization to impact HSV-2 latency and associated pathogenesis

影响 HSV-2 潜伏期和相关发病机制的治疗性免疫接种

基本信息

批准号：
8731793
负责人：
Nigel Bourne
金额：
$ 23.25万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-09 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8731793
关键词：
Address Adult Affect Algorithms American Animal Model Antigens Antiviral Agents Antiviral Therapy Area Awareness Biological Assay Birth CD8B1 gene Cavia Cells Clinical Clinical Trials Confocal Microscopy DNA Vaccines Developing Countries Development Disease Epithelial Epithelium Event Female Frequencies Ganglia Genital system Goals HIV Herpes Simplex Virus Vaccines Human Human Herpesvirus 2 Image Imaging Techniques Immune Immune response Immunization Incidence Individual Infection Latent Virus Latent virus infection phase Link Measures Mediating Methodology Methods Modeling Modification Molecular Virology Morbidity - disease rate Mothers Neurons Newborn Infant Pathogenesis Pathology Population Population Sizes RNA Reagent Recurrence Recurrent disease Regimen Resolution Risk Severities Sexually Transmitted Diseases Simplexvirus Site Spinal Cord Symptoms T-Lymphocyte Techniques Testing Therapeutic Therapeutic Uses Time Tissues Vaccination Vaccines Vagina Viral Pathogenesis Viral load measurement Virus Virus Latency Virus Shedding Work base calreticulin cell mediated immune response design and construction disease transmission enzyme linked immunospot assay experience genital herpes human disease immunogenicity immunoregulation improved latent infection mathematical model neonate novel novel vaccines optical imaging prevent prophylactic public health relevance reactivation from latency therapeutic vaccine transmission process vaccine efficacy

项目摘要

DESCRIPTION (provided by applicant): Approximately 16% of adult Americans have been infected by herpes simplex virus type 2 (HSV-2), the main cause of genital herpes. The virus establishes a lifelong latent infection from which it periodically reactivates and returns to the periphery where it can cause recurrent disease or be shed without clinical symptoms, resulting in efficient transmission to new individuals. Transmission of HSV-2 from mother to neonate at birth results in serious morbidity. Further, HSV-2 infections have been shown to increase the risk of HIV acquisition by 2 to 4- fold. Immunization would be the most effective approach to preventing genital herpes, but prophylactic vaccines to protect against HSV-2 disease have failed in clinical trials. Clearly new strategies are needed. Therapeutic immunization has the potential to adapt and improve normal host antiviral immune responses and impact the pathological consequences associated with a latent HSV-2 infection. Consequently, the studies that we propose in this application address a significant clinical problem which is of direct relevance to this RFA. Here we will explore the use of therapeutic immunization to reduce the burden of latent virus infection, to limit reactivation from latency, or to quickly limit the repliation of reactivated virus reducing damage in the host. Guinea pigs are the only well characterized animal model which experience spontaneous reactivation events during latent HSV-2 infection resulting in recurrent virus shedding and clinical signs similar to human disease. Thus, they represent the best model to test hypotheses of immune modulation of HSV-2 latency. Our long term goal is to develop a therapeutic vaccine approach that will reduce the burden of latent HSV-2 infection and the pathogenesis associated with the latent infection. The objective of this application is to optimize delivery of a therapeutic HSV-2 vaccine and immune, imaging, and molecular virology techniques to quantify host responses and viral pathogenesis events both at the neuronal site of HSV-2 latency and in genital tissue the site of HSV-2 re-emergence. Our central hypothesis is that therapeutic immunization with a DNA vaccine can be used to impact the establishment of HSV-2 latency and will decrease recurrent genital disease as well as the magnitude and frequency of HSV-2 shedding. Aim 1 will develop powerful new techniques to quantify important cell-mediated immune events at the neuronal site of HSV-2 latency and at the genital site of re-emergence from latency. Aim 2 will utilize these newly developed methods to determine if therapeutic immunization at the onset of primary clinical disease will improve the efficacy of a candidate therapeutic HSV-2 vaccine, resulting in significantly lower latent virus load and diminished recurrent disease. Aim 3 will establish new imaging techniques to increase our understanding of the pathogenesis of HSV-2 following re-emergence from latency and to provide important quantitative algorithms to accurately measure the effect of reactivating virus on the genital epithelium. Aim 4 will develop novel vaccine constructs designed to increase cell-mediated immune responses to immunization and to more effectively interfere with HSV-2 latency and reactivation.

描述（由申请人提供）：大约16％的成年美国人被单纯疱疹病毒2型（HSV-2）感染，这是生殖器疱疹的主要原因。该病毒建立了一种终生的潜在感染，它会从中定期重新激活并返回到周围，在那里它会引起复发性疾病或没有临床症状，从而有效地传播给了新个体。 HSV-2在出生时从母亲到新生儿的传播导致严重发病。此外，HSV-2感染已被证明可将HIV获取的风险增加2至4倍。免疫将是预防生殖器疱疹的最有效方法，但是预防性疫苗可预防HSV-2疾病，在临床试验中已经失败了。显然需要新的策略。治疗性免疫有可能适应和改善正常宿主抗病毒免疫反应并影响与潜在HSV-2感染相关的病理后果。因此，我们在本申请中提出的研究解决了与此RFA直接相关的重大临床问题。在这里，我们将探讨使用治疗性免疫以减轻潜在病毒感染的负担，以限制潜伏期的重新激活，或迅速限制重新激活的病毒的重复降低宿主中的损害。豚鼠是唯一具有特征性的动物模型，在潜在的HSV-2感染期间经历自发性重新激活事件，导致复发性病毒脱落和类似于人类疾病的临床体征。因此，它们代表了测试HSV-2潜伏期免疫调节假设的最佳模型。我们的长期目标是开发一种治疗性疫苗方法，该方法将减轻潜在的HSV-2感染负担以及与潜在感染相关的发病机理。该应用的目的是优化治疗性HSV-2疫苗和免疫，成像和分子病毒学技术，以量化HSV-2潜伏期的神经元位点和生殖器组织中的宿主反应和病毒发病机理，HSV-2重新启动的部位。我们的中心假设是，使用DNA疫苗的治疗性免疫可用于影响HSV-2潜伏期的建立，并将减少复发性生殖器疾病以及HSV-2脱落的大小和频率。 AIM 1将开发强大的新技术，以量化HSV-2潜伏期神经元位点的重要细胞介导的免疫事件以及潜伏期重新出现的生殖器。 AIM 2将利用这些新开发的方法来确定原发性临床疾病发作时的治疗性免疫是否会提高候选治疗性HSV-2疫苗的疗效，从而导致潜在病毒负荷明显降低并减少复发性疾病。 AIM 3将建立新的成像技术，以增加我们对潜伏期重新出现后HSV-2发病机理的理解，并提供重要的定量算法，以准确测量将病毒重新激活生殖器上皮的影响。 AIM 4将开发新型的疫苗构建体，旨在增加细胞介导的免疫反应，并更有效地干扰HSV-2潜伏期和重新激活。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Development of disease and immunity at the genital epithelium following intrarectal inoculation of male guinea pigs with herpes simplex virus type 2.

雄性豚鼠直肠内接种 2 型单纯疱疹病毒后生殖器上皮疾病和免疫力的发展。

DOI：
10.1016/j.virol.2018.10.023
发表时间：
2019
期刊：
Virology
影响因子：
3.7
作者：
Bourne,Nigel;Banasik,BrianneN;Perry,ClariceL;Miller,AaronL;White,Mellodee;Pyles,RichardB;Milligan,GreggN
通讯作者：
Milligan,GreggN

Virus-specific immune memory at peripheral sites of herpes simplex virus type 2 (HSV-2) infection in guinea pigs.

DOI：
10.1371/journal.pone.0114652
发表时间：
2014
期刊：
PloS one
影响因子：
3.7
作者：
Xia J;Veselenak RL;Gorder SR;Bourne N;Milligan GN
通讯作者：
Milligan GN

Development and utilization of a custom PCR array workflow: analysis of gene expression in mycoplasma genitalium and guinea pig (Cavia porcellus).

DOI：
10.1007/s12033-014-9813-6
发表时间：
2015-02
期刊：
MOLECULAR BIOTECHNOLOGY
影响因子：
2.6
作者：
Veselenak, Ronald L.;Miller, Aaron L.;Milligan, Gregg N.;Bourne, Nigel;Pyles, Richard B.
通讯作者：
Pyles, Richard B.

Detection of herpes simplex virus type 2 (HSV-2) -specific cell-mediated immune responses in guinea pigs during latent HSV-2 genital infection.

检测豚鼠潜伏 HSV-2 生殖器感染期间单纯疱疹病毒 2 型 (HSV-2) 特异性细胞介导的免疫反应。

DOI：
10.1016/j.jim.2016.09.004
发表时间：
2016
期刊：
Journal of immunological methods
影响因子：
2.2
作者：
Perry,ClariceL;Banasik,BrianneN;Gorder,SummerR;Xia,Jingya;Auclair,Sarah;Bourne,Nigel;Milligan,GreggN
通讯作者：
Milligan,GreggN