Immune Correlates of Protection in Drug-Resistant HIV

描述（由申请人提供）：我在寻求K23奖的目标是调查艾滋病毒感染和发展转化研究的职业生涯。我的特别研究兴趣是在一个有效的预防或治疗艾滋病毒疫苗所需的重要免疫反应的确定。我已经组建了一个由国际公认的科学家组成的指导委员会，他们在转化研究方面有着良好的记录;我将获得临床研究方法方面的培训和免疫学方法方面的额外实验室培训;我计划开展一系列指导研究项目，这些项目将为我提供机会，获得成为一名富有成效的独立临床研究人员所需的“动手”培训。 许多HIV感染者尽管接受了抗逆转录病毒治疗，但HIV病毒复制水平很低。这种病毒血症代表复制能力降低的耐药病毒。这些患者维持增加的CD 4 + T细胞计数。然而，这些患者中有很大一部分最终会发展为高水平的病毒血症。我感兴趣的是研究可以预测哪些患者可能发展为高水平病毒血症的免疫学参数，以及研究耐药病毒血症对整个免疫系统的影响。我提出了以下具体目标：（1）评估较高的HIV特异性CD 4+和CD 8 + T细胞应答是否与抗逆转录病毒治疗患者耐药HIV复制的控制有关;（2）评估免疫系统老化的证据是否与抗逆转录病毒治疗部分控制病毒血症患者的CD 4 + T细胞丢失有关;（3）评估在接受抗逆转录病毒治疗的部分控制病毒血症患者中，T细胞对免疫应答的能力是否改变。我们假设维持高水平的艾滋病毒特异性T细胞反应将预测病毒血症的部分控制的维持;我们将纵向跟踪这些患者，对艾滋病毒特异性T细胞功能进行系列测量。此外，部分HIV病毒血症的存在与效应CD 4 + T细胞的比例增加有关，这是免疫系统老化的标志。我们假设这些患者将持续CD 4 + T细胞丢失;我们将对他们进行T细胞免疫表型的系列测量。此外，我们假设部分病毒血症控制的患者对免疫的反应降低，这是体内免疫能力的估计。对于目标1和2，我将使用在已建立的队列研究中收集的样本。对于目标3，我将进行一项前瞻性干预性研究，在该研究中，我将设计并实施一项独立的临床研究项目。

DESCRIPTION (provided by applicant): My goals in seeking a K23 award are to investigate HIV infection and to develop a career in translational research. My particular research interest is in the determination of important immune responses needed in an effective preventative or therapeutic HIV vaccine. I have assembled a mentoring committee composed of internationally recognized scientists with strong track records in translational research; I will obtain training in clinical research methodologies and additional laboratory training in immunologic methodologies; and I propose to conduct a series of mentored research projects that will provide opportunities for me to acquire the "hands-on" training needed to become a productive, independent clinical researcher. Many HIV-infected patients have low levels of HIV viral replication despite antiretroviral therapy. This viremia represents drug-resistant virus with reduced replicative capacity. These patients maintain increased CD4+ T cell counts. A significant proportion of these patients, however, will ultimately develop high-level viremia. I am interested in investigating the immunologic parameters that may predict which patients may develop high-level viremia, as well as study the effect of drug-resistant viremia on the entire immune system. I propose the following specific aims: (1) To assess whether higher HIV-specific CD4+ and CD8+ T cell responses are associated with the control of drug-resistant HIV replication in patients on antiretroviral therapy; (2) To assess whether evidence of an aging immune system is associated with CD4+ T cell loss in patients with partially controlled viremia on antiretroviral therapy; (3) To assess whether the ability of T cells to respond to immunization is altered in patients with partially controlled viremia on antiretroviral therapy. We hypothesize that the maintenance of high-level HIV-specific T cell responses will predict maintenance of partial control of viremia; we will follow these patients longitudinally with serial measurements of HIV-specific T cell function. Furthermore, the presence of partial HIV viremia is associated with an increased proportion of effector CD4+ T cells, a sign of an aging immune system. We hypothesize that these patients will sustain CD4+ T cell loss; we will follow them with serial measurements of T cell immunophenotyping. In addition, we hypothesize that patients with partial viremic control will have reduced responses to immunization, an estimate of in vivo immune competence. For Aims 1 and 2, I will use samples collected in an established cohort study. For Aim 3, I will conduct a prospective interventional study, where I will design and implement an independent clinical research project.