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

 描述(由申请人提供)：在14-49岁的美国人中，目前约有16%的人是单纯疱疹病毒2型(HSV-2)血清阳性者，全球每年有2300万新感染病例。新生儿和免疫受损个体的感染会导致严重的发病率或死亡。此外，单纯疱疹病毒2型感染增加了感染艾滋病毒的风险。免疫接种将是控制HSV-2最有效的方法，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失败了。用HSV-2感染的小鼠和人类进行的临床前研究表明，生殖器上皮中病毒感染部位的病毒特异性T细胞的存在可能是有效保护生殖器上皮的关键。这些细胞位于战略位置，以防止再次感染，并干扰HSV-2在生殖道中的脱落，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，常驻生殖器的记忆T细胞可能决定HSV-2脱落的持续时间，而通过治疗刺激这些细胞可能会影响病毒的脱落；然而，缺乏对这种保护作用的明确证明。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，需要一个准确反映HSV-2在人类身上发生的致病事件的动物模型。豚鼠是唯一一种常见的实验动物，在潜伏的HSV-2感染期间经历了自发的重新激活和病毒脱落事件，这与感染的人类经历的类似，是检验HSV-2反复脱落的免疫调节假说的最佳模型。使用这个模型，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脱落过程中限制阴道上皮感染的程度中发挥关键作用。此外，通过复制缺陷HSV-2疫苗的治疗性免疫可以有效地提高该细胞群体的数量。我们的长期目标是开发治疗性疫苗，提高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疾病的侵袭，并控制确实感染HSV-2的个人的复发HSV-2脱落，从而影响HSV-2传播。这项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。目的1将确定生殖器驻留的、HSV特异性记忆T细胞在改变HSV-2自然重新激活后HSV-2脱落的频率和/或幅度中的作用。目的2将确定治疗性免疫在调节复发疾病和病毒脱落方面的效果是否可以通过特别提高HSV特异性生殖器驻留T细胞的数量来优化。这项工作意义重大，因为了解病毒特异性T细胞在HSV-2脱落部位的基因组束中的作用对于开发减少HSV-2传播的治疗性疫苗至关重要。

 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.