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

• 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
• 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' 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

 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（由申请人提供）：目前，14-49 岁的美国人中约有 16% 的 2 型单纯疱疹病毒 (HSV-2) 血清呈阳性，全世界每年新增感染人数为 2300 万。新生儿和免疫受损个体的感染会导致严重的发病或死亡。此外，HSV-2 感染会增加感染 HIV 的风险。免疫接种将是控制 HSV-2 的最有效方法，但引发针对 HSV-2 的全身免疫反应的预防性疫苗在临床试验中却失败了。对 HSV-2 感染小鼠和人类的临床前研究表明，生殖器上皮病毒感染部位存在病毒特异性 T 细胞可能对于有效保护生殖器上皮至关重要。这些细胞的策略性定位是为了防止再次感染并干扰生殖道中 HSV-2 的脱落，从而影响 HSV-2 的传播。这些细胞与重新激活的病毒相互作用的数学模型表明，生殖器驻留记忆T细胞可能决定HSV-2脱落的持续时间，并且治疗上刺激这些细胞可能会影响病毒脱落；然而，这种保护作用缺乏明确的证明。要了解这些细胞在调节 HSV-2 脱落中的功能以及如何用疫苗诱导这些细胞，需要一个能够准确反映人类中发生的 HSV-2 致病事件的动物模型。豚鼠是唯一一种在潜伏的 HSV-2 感染期间经历自发重新激活和病毒脱落事件的常见实验动物，这些事件与受感染的人类经历的情况相似，并且代表了测试 HSV-2 反复脱落的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发挥着关键作用。此外，通过使用复制缺陷型HSV-2疫苗进行治疗性免疫，可以有效增强该细胞群的数量。我们的长期目标是开发治疗性疫苗，增强 HSV 特异性生殖道驻留 T 细胞的数量和功能，以保护女性生殖粘膜免受复发性疾病的侵害，并控制已感染个体的复发性 HSV-2 脱落，从而影响 HSV-2 传播。本应用的目的是了解病毒特异性生殖器驻留 T 细胞对 HSV-2 从潜伏期重新激活后病毒脱落的影响。目标 1 将确定生殖器驻留的 HSV 特异性记忆 T 细胞在改变自然 HSV-2 重新激活后 HSV-2 脱落的频率和/或幅度中的作用。目标 2 将确定是否可以通过特异性增强 HSV 特异性生殖器驻留 T 细胞群的数量来优化治疗性免疫在调节复发性疾病和病毒脱落方面的功效。这项工作意义重大，因为了解生殖道中 HSV-2 脱落部位的病毒特异性 T 细胞的作用对于开发治疗性疫苗以减少 HSV-2 传播至关重要。