T cell functionality and control of HIV infection

描述(申请人提供)：在这份R01续期申请中，我们建议继续我们的工作，研究T细胞功能在控制急性和慢性艾滋病毒感染中的作用，目的是开发可应用于艾滋病毒疫苗开发的有意义的艾滋病毒感染保护相关性。在这里，我们将集中在转录因子T-bet和eomesodermin(eomesodermin，eomesodermin)对CD8+T效应细胞和CD4+T辅助细胞-1功能的调节，以了解HIV特异性T细胞免疫反应在急、慢性HIV感染中的失败。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。以前我们已经证明，在慢性HIV感染中，HIV特异性CD8+T细胞中T-bet的低表达与CD8+T细胞应答差和未能控制HIV病毒血症有关。我们的初步数据显示，尽管在急性HIV感染期间，大量(40-75%的T细胞)急性效应者CD8+T细胞反应增强，但这些反应不能维持，可能是因为它们未能在反应细胞内上调和正确定位T-bet或eome，最终导致未能控制病毒血症。在这段时间内，表达HIV特异的CD4+T细胞的T-bet在感染后的几周内就会丢失，这表明T辅助1型反应的迅速丧失对于产生和维持有效的CD8+T细胞反应和抗体反应至关重要。然而，重要的是，在HIV精英控制器中，T-bet的表达在HIV特异性的CD4+和CD8+T细胞中都保持不变，这表明这些反应在有效的HIV特异性免疫反应中发挥了关键作用。基于这些前提，我们假设一种成功的HIV疫苗将需要依赖于T-bet/eome的HIV特异性CD8和CD4Th1反应的刺激，以中介清除或控制最初的病毒血症。因此，在这一应用中，我们将重点研究控制HIV病毒血症的CD8+和CD4Th1T细胞反应，这些反应的转录调控，以及不同的疫苗/佐剂策略是否可以诱导这些类型的反应。在目标1中，我们将确定CD8+T细胞效应器功能与T-bet/eome在HIV急性、慢性和非进行性感染中的表达和定位的关系，以及它们与长期控制病毒血症的关系。在目标2中，我们将确定在急性、慢性和非进行性感染中表达CD4+Th1 T细胞的T-bet/eome的诱导和维持，以及它们如何与HIV特异性CD8+T细胞应答的质量和CD8+T细胞效应功能的维持直接相关。最后，在目标3中，我们将确定T-bet和eome通过当前的HIV疫苗和佐剂策略在人类和恒河猴的CD4+和CD8+T细胞中进行调节的潜力，以应用于预防性和治疗性(基于治愈的)HIV疫苗的开发。

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.