Immune Correlates of Protection in Drug-Resistant HIV

描述(由申请者提供)：我申请K23奖项的目标是调查艾滋病毒感染情况，并在翻译研究方面发展事业。我特别感兴趣的研究是确定有效的预防性或治疗性艾滋病毒疫苗所需的重要免疫反应。我已经组建了一个由在翻译研究方面拥有良好记录的国际公认的科学家组成的指导委员会；我将获得临床研究方法学的培训和免疫学方法学的额外实验室培训；我建议开展一系列指导研究项目，这些项目将为我提供机会，使我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。 尽管接受了抗逆转录病毒治疗，但许多艾滋病毒感染者的艾滋病毒复制水平很低。这种病毒血症代表复制能力降低的抗药性病毒。这些患者的CD4T细胞计数持续增加。然而，这些患者中的相当大一部分最终会发展为高水平的病毒血症。我感兴趣的是研究免疫学参数，这些参数可以预测哪些患者可能发展为高水平的病毒血症，以及研究抗药性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)评估更高的HIV特异性CD4和CD8 T细胞应答是否与抗逆转录病毒治疗患者中耐药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中部分控制的病毒血症患者的CD4T细胞丢失有关；(3)评估抗逆转录病毒治疗中部分控制的病毒血症患者的T细胞对免疫应答的能力是否发生改变。我们假设，维持高水平的HIV特异性T细胞反应将预示病毒血症部分控制的维持；我们将纵向跟踪这些患者，对HIV特异性T细胞功能进行连续测量。此外，部分HIV病毒血症的存在与效应者CD4T细胞比例的增加有关，这是免疫系统老化的标志。我们假设这些患者将遭受CD4T细胞丢失；我们将在他们之后进行T细胞免疫表型的系列测量。此外，我们假设部分病毒控制的患者对免疫的反应会降低，这是对体内免疫能力的估计。对于目标1和目标2，我将使用在既定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研究，在那里我将设计和实施一个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.