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

 描述（由申请人提供）：目前约16%的14-49岁的美国人对2型单纯疱疹病毒（HSV- 2）呈血清阳性，全球每年发生2300万例新感染。新生儿和免疫受损个体的感染导致严重的发病率或死亡。此外，HSV-2感染增加了获得HIV的风险。免疫接种是控制HSV-2最有效的方法，但引发针对HSV-2的全身免疫应答的预防性疫苗在临床试验中失败。对HSV-2感染的小鼠和人的临床前研究表明，生殖器上皮中病毒感染部位的病毒特异性T细胞的存在对于生殖器上皮的有效保护可能是至关重要的。这些细胞被战略性地定位以防止再感染并干扰生殖道中的HSV-2脱落，从而影响HSV-2传播。这些细胞与再活化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，刺激这些细胞治疗可能会影响病毒脱落;然而，缺乏这种保护作用的明确证明。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准确反映HSV-2在人类中发生的致病事件的动物模型。豚鼠是在潜伏HSV-2感染期间经历自发再活化和病毒脱落事件的唯一常见实验室动物，其与受感染的人类经历的事件相似，并且代表了测试HSV-2复发性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/或幅度以及在HSV-2脱落事件期间限制阴道上皮感染的程度中起关键作用。此外，通过用复制缺陷型HSV-2疫苗进行治疗性免疫，可以有效地增强该细胞群的数量。我们的长期目标是开发治疗性疫苗，其将增强HSV特异性生殖道驻留T细胞的数量和功能，以保护女性生殖器粘膜免受复发性疾病的影响，并控制感染个体中的复发性HSV-2脱落，从而影响HSV-2传播。本申请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。目的1将确定生殖器驻留的HSV特异性记忆T细胞在自然HSV-2再活化后改变HSV-2脱落的频率和/或幅度中的作用。目的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细胞群的大小来优化治疗性免疫在调节复发性疾病和病毒脱落中的功效。这项工作是重要的，因为了解病毒特异性T细胞在生殖道HSV-2脱落部位的作用对于开发治疗性疫苗以减少HSV-2传播至关重要。

 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.