IMPACT OF TUBERCULOSIS ON THE HIV RESERVOIR

结核病对艾滋病病毒库的影响

• 批准号: 10483895
• 负责人: George Kyei
• 金额: $ 14.52万
• 依托单位: UNIVERSITY OF GHANA MEDICAL CENTRE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-22 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10483895
• 关键词: Affect; African; Agonist; Antigens; Attention; Biological; Biological Assay; Blood; Bromodomain; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cells; Clinical; Clonal Expansion; Coculture Techniques; Color; Country; DNA; Disease remission; Drug resistance; Ensure; Flow Cytometry; Future; GTP-Binding Protein alpha Subunits, Gs; Ghana; HIV; HIV-1; HIV/TB; HLA-DR Antigens; Histone Deacetylase Inhibitor; IL2RA gene; Immune response; Immunologics; Interferon Type II; Interferon-alpha; Interleukin-1 beta; Interleukin-10; Interleukin-17; Interleukin-2; Interleukin-6; Investigation; Knowledge; Life Expectancy; Light; Measures; Methods; Modeling; Mycobacterium tuberculosis antigens; Patients; Peptides; Pharmaceutical Preparations; Production; Protein Kinase C; Proviruses; Quantitative Reverse Transcriptase PCR; Radiology Specialty; Research; Response Latencies; Rest; Shock; T cell response; T-Lymphocyte; TNF gene; Testing; Tuberculosis; Viral; Viral Load result; Viral reservoir; Virus; antiretroviral therapy; biomarker panel; chimeric antigen receptor; co-infection; cohort; cost; cytokine; exhaustion; inhibitor; interleukin-22; latent HIV reservoir; neutralizing antibody; programmed cell death protein 1; programs; reactivation from latency; receptor vaccine; recruit; response; side effect; therapeutic vaccine; viral RNA

PROJECT SUMMARY Even though antiretroviral therapy (ART) can suppress HIV and increase life expectancy, it does not provide cure. Patients must commit to daily medications and deal with side effects, unsustainable costs and drug resistance. The main obstacle to an HIV cure is persistent provirus in the resting CD4+ T cell reservoir which produce virus under the right stimulation conditions. The most popular approaches for HIV cure or remission such as the shock and kill approach, broadly neutralizing antibodies, chimeric antigen receptors and therapeutic vaccines will all require some form of reactivation of the latent provirus. However, tuberculosis, an important factor that could affect the viral reservoir and its response to latency reversing agents (LRAs) has not received much attention in the context of HIV cure research. Over a third of HIV patients are infected with TB. Tuberculosis, including latent TB infection (LTBI), produces antigens that stimulate T cells, which could result in proliferation and alter the response of the reservoir to LRAs. Persistent stimulation could also result in T cell exhaustion. We are working with the hypothesis that TB antigens in the blood of co-infected patients stimulate T cells to increase the size of the reservoir and alter the responses of CD8+ and CD8+ T cells. We will investigate this hypothesis with the following specific aims: Aim 1: Identify differences in T cell responses between HIV and HIV/LTB patients. We hypothesize that in co- infected patients, CD4+ T cells will have decreased responses to LRA and CD8+ T cells will have reduced killing ability upon stimulation. First, we will compare the baseline activation status of resting T cells from virologically suppressed patients (VL <50 copies per ml) with HIV or HIV/LTBI. Second, we will stimulate the CD4+ and CD8+ T cells in each group for the production of relevant cytokines and the expression of the activation and exhaustion markers. Third, we will isolate resting T cells from patients and stimulate them with different LRAs. Fourth, we will determine the capacity of CD8+ T cells from co-infected patients to kill reactivated CD4+ T cells expressing HIV-1 antigens. Aim 2: Determine the size of the HIV reservoir in HIV only and HIV/LTB co-infected patients. We hypothesize that co-infected patients will have a larger reservoir size due to persistent stimulation that results in further CD4+ T cell seeding or clonal expansion. We will recruit 75 HIV only patients and 75 HIV-TB patients from our cohort with a viral load of <50 copies per ml for more than 2 years. We will isolate resting T cells to measure the size of the reservoir using the IPDA assay which measures only intact proviruses with potential to produce virus. This project will provide critically missing knowledge and understanding of how T cells in patient co-infected with TB respond to latency reversing agents, and give an indication on the size of the HIV reservoir in these patient. Information gained will be crucial in planning HIV cure studies in co-infected patients.

项目摘要 尽管抗逆转录病毒疗法（ART）可以抑制艾滋病毒并延长预期寿命，但它并不能提供 疗方患者必须承诺每天服药，并处理副作用，不可持续的费用和药物 阻力HIV治愈的主要障碍是静止的CD 4 + T细胞库中的持续性前病毒， 在合适的刺激条件下产生病毒。最流行的艾滋病毒治愈或缓解方法 例如休克和杀死方法、广泛中和抗体、嵌合抗原受体和治疗剂 疫苗都需要某种形式的潜伏原病毒的再活化。 然而，结核病，一个重要的因素，可能会影响病毒的水库和其反应的潜伏期 逆转剂（LRA）在HIV治愈研究的背景下没有受到太多关注。超过三分之一的艾滋病毒 患者感染结核病。结核病，包括潜伏性结核感染（LTBI），产生抗原，刺激 T细胞，这可能导致增殖并改变水库对LRA的反应。持续刺激 也可能导致T细胞衰竭。 我们正在研究这样的假设：合并感染患者血液中的结核抗原刺激T细胞， 增加储库的大小并改变CD 8+和CD 8 + T细胞的反应。我们会调查的 假设，具体目标如下： 目的1：确定HIV和HIV/LTB患者之间T细胞反应的差异。我们假设，在共同- 在感染患者中，CD 4 + T细胞对LRA的应答降低，CD 8 + T细胞对LRA的杀伤降低， 能力，刺激。首先，我们将从病毒学角度比较静息T细胞的基线活化状态， HIV或HIV/LTBI抑制患者（VL <50拷贝/ml）。第二，我们将刺激CD 4+和CD 8 + 各组T细胞对相关细胞因子的产生及表达的活化和耗竭 标记。第三，我们将从患者中分离出静息T细胞，并用不同的LRA刺激它们。四是 将确定来自共感染患者的CD 8 + T细胞杀死表达CD 4 + T细胞的再活化的能力。 HIV-1抗原。 目的2：确定HIV单独感染和HIV/LTB合并感染患者中HIV储存库的大小。我们假设 由于持续刺激，合并感染的患者将具有更大的储库大小，导致进一步的CD 4 + T细胞接种或克隆扩增。我们将从我们的队列中招募75名HIV患者和75名HIV-TB患者 病毒载量<50拷贝/ml超过2年。我们将分离静息T细胞， 使用仅测量具有产生病毒潜力的完整前病毒的IPDA测定来检测储库。 该项目将提供关键缺失的知识和理解如何在病人的T细胞共感染 TB对潜伏期逆转剂有反应，并指示这些患者中HIV储存库的大小。 获得的信息将是至关重要的计划艾滋病毒治疗研究的合并感染的患者。