The impact of HIV adaptation to CD8 T cells on infection and viral control

项目总结 HIV-1序列多样性是开发有效的预防性药物的一个巨大障碍 治疗性HIV-1疫苗。从CD8 T细胞介导的免疫压力中逃脱或适应是主要的 病毒多样性的贡献者。经调整的表位(AE)编码与人类白细胞抗原I类(HLA-I)相关的逃逸 突变，而其对应的非适应表位(NAE)不包含任何与HLA-I相关的证据 突变或CTL逃逸。我们之前的研究表明，感染高度适应的HIV-1毒株与 临床结果很差。造成病毒控制受损的确切机制(S)尚不清楚 理解和理解是本研究的重点。尽管AE在急性HIV感染和 接种疫苗后，我们的初步数据显示，CD8-AE在慢性HIV感染期间存在；然而， 这些CD8-AE在急性和慢性感染中通常是低亲和力反应。纵向序列 分析表明，这些AE没有经历额外的逃逸突变或回复到NAE形式，尽管 来自CD8-AE的免疫压力。我们的初步数据还表明，低亲和力免疫反应可以 诱导致炎树突状细胞(DC)表型，能够反式感染CD4T细胞。基于这些 研究发现，我们的前提是，功能不佳的CD8-AE正在赋予病毒式健康优势。我们的 假设CD8-AE通过不能有效地杀死被感染的细胞从而参与HIV的发病 创造一种炎症环境，以DC依赖的方式促进艾滋病毒的扩散。为了测试这一点 假设，我们将使用从人类(艾滋病毒感染和疫苗接种研究)和BLT-小鼠获得的样本 感染艾滋病毒，从而进行互补的体外和体内研究。在目标1中，我们将确定 NAE和AE诱导的CD8T细胞应答质量。我们将测试CD8-NAE和AE-特异性的质量 分析一组急性感染患者在接受抗逆转录病毒治疗6个月后的反应 (ART)除了接受编码许多AEs的马赛克疫苗的艾滋病毒血清阴性者外。在目标2中， 我们将确定AE特异的CD8T细胞是否诱导促炎的DC表型，从而增强CD4 T细胞反式感染。我们将鉴定和比较CD8-NAE和AE特异性细胞诱导 使用从急性感染和疫苗接种研究中获得的样本的炎症性DC表型。最后， 目的3将确定感染编码AEs的HIV是否会加剧急性期病毒载量动力学和 导致体内人源化BLT小鼠模型的炎症状态增强。总而言之，这个角色 HIV适应在CD8 T细胞功能中的作用研究相对较少。我们的建议将有助于确定 HIV特异性CD8 T细胞能否被优化以控制病毒感染并为 未来的疫苗防治策略。 。 。

PROJECT SUMMARY HIV-1 sequence diversity presents a formidable obstacle in the development of an efficacious preventative or therapeutic HIV-1 vaccine. Escape or adaptation from CD8 T cell mediated immune pressure is a major contributor to viral diversity. An adapted epitope (AE) encodes an HLA class I (HLA-I) associated escape mutation, while its counterpart non-adapted epitope (NAE) does not contain any evidence of HLA-I associated mutation or CTL escape. We previously showed that infection with a highly adapted HIV-1 strain was associated with a poor clinical outcome. The precise mechanism(s) responsible for this impaired viral control are not yet understood and is the focus of this study. Although AE are poorly immunogenic in acute HIV infection and following vaccination, our preliminary data show that CD8-AE are present during chronic HIV infection; however, these CD8-AE are generally low avidity responses in both acute and chronic infection. Longitudinal sequence analysis shows that these AEs do not undergo additional escape mutations or revert to the NAE form, despite immune pressure from CD8-AE. Our preliminary data also demonstrated that low avidity immune responses can induce a pro-inflammatory dendritic cell (DC) phenotype capable of trans-infecting CD4 T cells. Based on these findings, our premise holds that poorly functioning CD8-AE are conferring a viral fitness advantage. Our hypothesis is that CD8-AE contribute to HIV pathogenesis by failing to efficiently kill infected cells and thus creating an inflammatory environment that promotes HIV proliferation in a DC-dependent manner. To test this hypothesis, we will use samples obtained from humans (HIV infection and vaccination studies) and BLT-mice infected with HIV, thereby performing complementary in vitro and in vivo studies. In aim 1, we will determine the quality of CD8 T cell responses induced by NAE and AE. We will test the quality of CD8-NAE and AE-specific responses by analyzing a cohort of patients with acute infection followed for 6 months off antiretroviral therapy (ART) in addition to HIV seronegative individuals who received a mosaic vaccine encoding many AEs. In aim 2, we will determine whether AE-specific CD8 T cells induce a pro- inflammatory DC phenotype that enhances CD4 T cell trans-infection. We will characterize and compare the ability of CD8-NAE and AE specific cells to induce an inflammatory DC phenotype using samples obtained from acute infection and vaccination studies. Finally, aim 3 will determine whether infection with HIV encoding AEs exacerbates acute phase viral load kinetics and leads to an enhanced inflammatory state in an in-vivo humanized BLT mouse model. In summary, the role that HIV adaptation plays in the function of CD8 T cells is relatively understudied. Our proposal will help determine whether HIV specific CD8 T cells can be optimized to control viral infection and provide valuable information for future vaccine prevention and cure strategies. . .