Induction, maintenance, and function of genital tract-resident CD8+ T cells

生殖道驻留 CD8 T 细胞的诱导、维持和功能

基本信息

批准号：
9094547
负责人：
Gregg N. Milligan
金额：
$ 38.75万
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：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2019-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9094547
关键词：
American Animal Model Antigens CD8B1 gene Cavia Cell Communication Cell physiology Cells Cellular Immunity Cessation of life Chronic Clinical Clinical Trials Development Disease Economic Burden Epithelium Event Female Frequencies Future Genital system Goals HIV Health Hepatitis B Virus Herpes Simplex Virus Vaccines Human Human Herpesvirus 2 Human Papillomavirus Immune Immune response Immunization Individual Infection Laboratory Animals Licensing Maintenance Mediating Memory Methods Modeling Morbidity - disease rate Mucous Membrane Mus Nature Newborn Infant Play Population Population Sizes Prevention Property Proteins Reagent Recurrence Recurrent disease Regimen Risk Role Route Sexually Transmitted Diseases Simplexvirus Site Symptoms T cell response T memory cell T-Lymphocyte Testing Therapeutic Therapeutic Effect Time Treatment Efficacy Ursidae Family Vaccines Vagina Viral Virus Virus Diseases Virus Replication Virus Shedding Woman Women&apos s Health Work aged base disorder control efficacy testing experience genital herpes genital infection health economics immunoregulation mathematical model neonate pathogen preclinical study prevent prophylactic reactivation from latency reproductive tract response seropositive therapeutic vaccine transmission process viral transmission virus development

项目摘要

DESCRIPTION (provided by applicant): Approximately 16% of Americans aged 14-49 are currently seropositive for Herpes simplex virus type 2 (HSV- 2) and worldwide, 23 million new infections occur each year. Infection of neonates and immune compromised individuals results in serious morbidity or death. Further, HSV-2 infections increase the risk of acquisition of HIV. Immunization would be the most effective approach to control HSV-2, but prophylactic vaccines that elicit systemic immune responses against HSV-2 have failed in clinical trials. Preclinical studies with HSV-2 infected mice and humans have suggested that the presence of virus-specific T cells at the site of viral infection in the genital epithelia may be critical for effectve protection of the genital epithelia. These cells are strategically located to protect against re-infection and to interfere with HSV-2 shedding in the genital tract thereby impacting HSV-2 transmission. Mathematical models of the interaction of these cells with the reactivated virus suggest that genital-resident memory T cells may determine the duration of HSV-2 shedding and that stimulating these cells therapeutically may impact virus shedding; however, a clear demonstration of this protective role is lacking. Understanding the function of these cells in modulation of HSV-2 shedding and how to induce these cells with vaccines requires an animal model that accurately reflects the pathogenic events of HSV-2 as they occur in humans. Guinea pigs are the only common laboratory animals that experience spontaneous reactivation and virus shedding events during latent HSV-2 infection that are similar to those experienced by infected humans and represent the best model to test hypotheses of immune modulation of HSV-2 recurrent shedding. Using this model, our central hypothesis is that these cells play a critical role in modulating the frequency and/or magnitude of HSV-2 shedding and in limiting the extent of vaginal epithelium infection during HSV-2 shedding events. Further, the magnitude of this cell population can be effectively enhanced by therapeutic immunization with a replication defective HSV-2 vaccine. Our long term goal is to develop therapeutic vaccines that will enhance the number and function of HSV-specific genital tract resident T cells to protect the female genital mucosa against recurrent disease and control recurrent HSV-2 shedding in individuals that do become infected, therefore impacting HSV-2 transmission. The objective of this application is to understand the impact of virus-specific genital-resident T cells on virus shedding after reactivation of HSV- 2 from latency. Aim 1 will determine the role of genital-resident, HSV-specific memory T cells in modifying the frequency and/or magnitude of HSV-2 shedding following natural HSV-2 reactivation. Aim 2 will determine if the efficacy of therapeutic immunization in modulating recurrent disease and virus shedding can be optimized by specifically enhancing the magnitude of HSV-specific genital-resident T cell populations. This work is significant because understanding the role of virus-specific T cells residing in the genita tract at the site of HSV-2 shedding will be critical for development of therapeutic vaccines to reduce HSV-2 transmission.

描述（由适用提供）：目前约有16％的14-49岁的美国人对单纯疱疹病毒2型（HSV-2）（HSV-2）和全球播放，每年发生2300万新感染。新生儿和免疫组合个体的感染导致严重的发病率或死亡。此外，HSV-2感染增加了获取HIV的风险。免疫将是控制HSV-2的最有效方法，但是在临床试验中，引起针对HSV-2的全身免疫反应的预防性疫苗失败了。对HSV-2感染小鼠和人类进行的临床前研究表明，生殖器上皮病毒感染部位的病毒特异性T细胞的存在可能对保护生殖器上皮的保护至关重要。这些细胞在战略上是为了防止重新感染并干扰生殖道中的HSV-2脱落，从而影响HSV-2的传播。这些细胞与重新激活病毒相互作用的数学模型表明，生殖器居民的记忆T细胞可能决定HSV-2脱落的持续时间，并热刺激这些细胞可能会影响病毒脱落。但是，缺乏对这种受保护作用的明确证明。了解这些细胞在HSV-2脱落调节中的功能以及如何用疫苗诱导这些细胞需要一种动物模型，该模型准确地反映了HSV-2在人类中发生的病原事件。豚鼠是在潜在的HSV-2感染期间经历赞助子反应和病毒脱落事件的唯一常见实验动物，与受感染人类经历的人相似，并代表了测试HSV-2复发性免疫调节假设的最佳模型。使用该模型，我们的中心假设是这些细胞在调节HSV-2脱落的频率和/或幅度以及限制HSV-2脱落事件期间阴道上皮感染的程度方面起着关键作用。此外，通过复制有缺陷的HSV-2疫苗，可以通过治疗性免疫来有效地增强该细胞群体的大小。我们的长期目标是开发治疗性疫苗，以增强HSV特异性生殖道居民T细胞的数量和功能，以保护女性生殖器粘膜免受复发性疾病的影响，并控制确实感染的个体中复发的HSV-2脱落，从而影响HSV-2传播。该应用的目的是了解病毒特异性生殖器居住的T细胞对HSV-2从潜伏期重新激活后对病毒脱落的影响。 AIM 1将确定生殖器居民，HSV特异性记忆T细胞在自然HSV-2重新激活后修改HSV-2脱落的频率和/或幅度中的作用。 AIM 2将通过专门增强HSV特异性生殖器居民T细胞种群的大小来确定热免疫在调节复发性疾病和病毒脱落中的有效性。这项工作是重要的，因为了解HSV-2脱落部位的生殖器区域中的病毒特异性T细胞的作用对于开发热疫苗以减少HSV-2传播至关重要。