Characterizing the therapeutic efficacy of CD8 T cell responses induced by the IL-15 superagonist ALT-803

项目摘要 我们没有艾滋病毒的疫苗或治愈方法。CD 8 T细胞对于HIV病毒血症的初始控制是必需的， 但是设计基于CD 8 T细胞的HIV疫苗的尝试遇到了挑战。这些包括 (1)引发针对HIV最具免疫原性区域的细胞免疫应答，和（2）增强 抗病毒免疫反应的功能在正确的位置，以遏制病毒复制。 该提议是我们最初R 01的更新，该提议测试了CD 8 T细胞靶向不变性的假设， 表位不能检测和破坏病毒感染的细胞。根据在测试期间生成的数据， 在资助期间，我们发表了4篇手稿，提交了4篇口头摘要，提交了7篇海报摘要， 举办了8次研讨会。我们发现，SIV的控制是延迟和不完全的，在缺乏CD 8 T细胞。 靶向SIV免疫原性最强区域的细胞。如果没有检测到有效的CD 8 T细胞， 在具有非保护性MHC等位基因的动物中抑制SIV复制，我们的研究提出了以下问题： 设计一种通用疫苗以激发靶向不变表位的CD 8 T细胞的可行性。 在上一个赠款期间，我们利用上一个R 01的资金， 观察到免疫调节性IL-15超激动剂ALT-803可以增强CD 8 T细胞功能， 促进既往接受过疫苗接种的猕猴中的病毒抑制，但未接受过疫苗接种的猕猴中的病毒抑制 动物从这些研究中收集的数据为我们检验以下假设奠定了基础， ALT-803治疗增强了疫苗诱导的记忆性CD 8 T细胞的抗病毒功能， 通过将IL-15应答性抗原特异性CD 8 T细胞募集至淋巴结以杀死感染的靶标， 细胞我们将通过比较疫苗中ALT-803介导的SIV抑制来检验这一假设， 幼稚和接种疫苗的猕猴。我们还建议表征响应的CD 8 T细胞 群体中的细胞，以确定接种疫苗的动物中ALT-803增强的记忆性CD 8 T细胞是否表现出 与指示IL-15增加的转录特征相关的抗病毒功能增加 JAK/STAT信号通路。这些数据将有助于确定 在具有非保护性MHC等位基因的动物中功能相关的抗病毒CD 8 T细胞。 我们的研究是相关的，因为ALT-803正在临床试验中用作抗肿瘤和抗病毒药物。 剂我们希望最大限度地发挥ALT-803的作用，以便在这些环境中最有效地使用它。 ALT-803的某些研究不能在人类中进行，包括我们提出的研究。 我们将特别评估是否有必要在SIV感染前接种ALT-803， 诱导SIV感染后功能活性的CD 8 T细胞。这是一种范式转换方法， 疫苗研究，因为它重视免疫能力强的人的预防性接种。 因此，干预措施在HIV+免疫缺陷个体中有效。

PROJECT SUMMARY We do not have a vaccine or a cure for HIV. CD8 T cells are necessary for initial control of HIV viremia, but attempts to design a CD8 T cell based HIV vaccine have been met with challenges. These include (1) eliciting cellular immune responses against the most immunogenic regions of HIV and (2) enhancing the function of antiviral immune responses at the right location to contain virus replication. This proposal is a renewal of our original R01 testing the hypothesis that CD8 T cells targeting invariant epitopes are unable to detect and destroy virally-infected cells. Based on the data generated during the grant period, we published 4 manuscripts, presented 4 oral abstracts, presented 7 poster abstracts, and delivered 8 seminars. We found that SIV control was delayed and incomplete in the absence of CD8 T cells targeting the most immunogenic regions of SIV. Without detecting effective CD8 T cells to suppress SIV replication in animals with non-protective MHC alleles, our study raises questions over the feasibility of designing a universal vaccine to elicit CD8 T cells targeting invariant epitopes. During the last grant period and using funds from the previous R01, we also made the remarkable observation that the immunomodulatory IL-15 superagonist ALT-803 could boost CD8 T cell function to promote virus suppression in macaques that received prior vaccination, but not in vaccine-naïve animals. The data gathered from these studies has laid the foundation for us to test the hypothesis that that ALT-803 treatment enhances the antiviral function of vaccine-elicited memory CD8 T cells by recruiting IL-15 responsive antigen-specific CD8 T cells to lymph nodes to kill infected target cells. We will test this hypothesis by comparing ALT-803 mediated suppression of SIV in vaccine- naïve and vaccinated macaques. We also propose to characterize the responding CD8 T cell population to determine if ALT-803 enhanced memory CD8 T cells in the vaccinated animals exhibit increased antiviral function that is associated with transcription signatures indicative of increased IL-15 signaling through the JAK/STAT pathway. Together these data will help identify the features of functionally relevant antiviral CD8 T cells in animals with non-protective MHC alleles. Our study is relevant because ALT-803 is being used in clinical trials as an anti-tumor and anti-viral agent. We want to maximize the effect of ALT-803 so that it is used most effectively in these settings. Certain studies of ALT-803 cannot be performed in humans, including the one that we have proposed. We will specifically evaluate whether vaccination BEFORE SIV infection is necessary for ALT-803 to elicit functionally active CD8 T cells AFTER SIV infection. This is a paradigm shifting approach for vaccine research, because it places a value on prophylactic vaccination of immunocompetent individuals so that interventions are effective in HIV+ immunocomprimised individuals.