T cell functionality and control of HIV infection

描述（由申请人提供）：在这个R01续期申请中，我们建议继续我们的工作，检查T细胞功能在控制急性和慢性HIV感染中的作用，目的是开发可应用于HIV疫苗开发的HIV感染保护的有意义的相关性。在这里，我们将重点关注转录因子T-bet和eomesdermin （eomes）对CD8+ T效应细胞和CD4+ T辅助型1细胞功能的调节，以了解急性和慢性HIV感染期间HIV特异性T细胞免疫反应的失败。我们将进一步研究不同疫苗和佐剂策略刺激这些关键转录因子表达的能力。先前我们已经证明，在慢性HIV感染中，HIV特异性CD8+ T细胞内T-bet的低表达与CD8+ T细胞反应不良和HIV病毒血症控制失败有关。我们的初步数据表明，尽管在急性HIV感染期间大量（40-75%的T细胞）急性效应CD8+ T细胞反应被提高，但这些反应不能维持，可能是由于它们不能上调和正确定位应答细胞中的T-bet或基因组，最终导致病毒血症控制失败。在同一时期，表达hiv特异性CD4+ T细胞的T-bet在感染后数周内消失，这表明对产生和维持有效的CD8+ T细胞反应和抗体反应至关重要的T辅助1型反应迅速消失。然而，重要的是，T-bet表达在HIV精英控制者的HIV特异性CD4+和CD8+ T细胞中保持，这表明这些反应在有效的HIV特异性免疫反应中起关键作用。基于这些前提，我们假设成功的HIV疫苗将需要刺激T-bet/eomes依赖性HIV特异性CD8效应物和CD4 Th1反应，以介导清除或控制初始病毒血症。因此，在本应用中，我们将重点关注在控制HIV病毒血症中定义效应CD8+和CD4 Th1 T细胞反应，这些反应的转录调控，以及这些类型的反应是否可以由不同的疫苗/佐剂策略诱导。在目标1中，我们将定义在HIV急性、慢性和非进展性感染中CD8+ T细胞效应功能和T-bet/eomes表达和定位之间的关系，以及它们如何与病毒血症的长期控制相关。在目标2中，我们将定义在急性、慢性和非进行性感染中表达CD4+ Th1 T细胞的T-bet/eomes的诱导和维持，以及这些与hiv特异性CD8+ T细胞反应的质量和CD8+ T细胞效应功能的维持之间的直接关系。最后，在Aim 3中，我们将定义通过当前的HIV疫苗和佐剂策略在人类和恒河猴CD4+和CD8+ T细胞中调节T-bet和基因组的潜力，以应用于预防性和治疗性（基于治愈的）HIV疫苗开发。

DESCRIPTION (provided by applicant): In this R01 renewal application, we propose to continue our work examining the role of T cell function in the control of acute and chronic HIV infection, for the purpose of developing meaningful correlates of protection in HIV infection that can be applied to HIV vaccine development. Here we will focus on the regulation of CD8+ T effector cell and CD4+ T helper type-1 cell function,by the transcription factors T-bet and eomesodermin (eomes), in order to understand the failings of the HIV-specific T cell immune response during acute and chronic HIV infection. We will further study the ability of different vaccine and adjuvant strategies to stimulate the expression of these key transcription factors. Previously we have shown that in chronic HIV infection, low expression of T-bet within HIV-specific CD8+ T cells is associated with poor effector CD8+ T cell responses and a failure to control HIV viremia. Our preliminary data demonstrates that although a massive (40-75% of T cells) acute effector CD8+ T cell response is raised during acute HIV infection, these responses cannot be maintained, perhaps due to their failure to upregulate and properly localize T-bet or eomes within responding cells, ultimately resulting in failure to control viremia. During this sam period, T-bet expressing HIV-specific CD4+ T cells are lost within weeks of infection, suggesting a rapid loss of T helper type 1 responses critical for the generation and maintenance of effective CD8+ T cell responses and antibody responses. Importantly however, T-bet expression is maintained in both HIV-specific CD4+ and CD8+ T cells in HIV elite controllers, suggesting that these responses play a key role in effective HIV-specific immune responses. Based upon these premises, we hypothesize a successful HIV vaccine will require stimulation of T-bet/eomes dependent HIV-specific CD8 effector and CD4 Th1 responses in order to mediate clearance or control of initial viremia. In this application we will therefore focus on defining effector CD8+ ad CD4 Th1 T cell responses in the control of HIV viremia, the transcriptional regulation of these responses, and whether these types of responses can be induced by different vaccine/adjuvant strategies. In Aim 1 we will define the relationship between CD8+ T cell effector function and T-bet/eomes expression and localization in HIV acute, chronic, and nonprogressive infection and how they relate to long-term control of viremia. In Aim 2, we will define the induction and maintenance of T-bet/eomes expressing CD4+ Th1 T cells in acute, chronic, and nonprogressive infection, and how these directly relate to the quality of the HIV-specific CD8+ T cell response and maintenance of CD8+ T cell effector function. Finally, in Aim 3, we will define the potential for T-bet and eomes to be modulated within human and rhesus macaque CD4+ and CD8+ T cells by current HIV vaccine and adjuvant strategies for application to both prophylactic and therapeutic (cure-based) HIV vaccine development.