IMPACT OF TUBERCULOSIS ON THE HIV RESERVOIR

结核病对艾滋病病毒库的影响

• 批准号: 10598608
• 负责人: George Kyei
• 金额: $ 14.36万
• 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 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10598608
• 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; Flow Cytometry; Future; Ghana; HIV; HIV-1; HIV/TB; HLA-DR Antigens; Histone Deacetylase Inhibitor; IL17 gene; IL2RA gene; Immune response; Immunologics; Interferon Type II; Interferon alpha; Interleukin-1 beta; Interleukin-10; Interleukin-2; Interleukin-6; Investigation; Knowledge; Life Expectancy; Measures; Methods; Modeling; Mycobacterium tuberculosis antigens; Patients; Peptides; Pharmaceutical Preparations; Production; Proliferating; 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 即使抗逆转录病毒疗法（ART）可以抑制艾滋病毒并增加预期寿命，但也无法提供 治愈。患者必须承诺每日药物并处理副作用，不可持续的成本和药物 反抗。 HIV治疗的主要障碍是静止的CD4+ T细胞库中的持久性病毒 在右刺激条件下产生病毒。艾滋病毒治愈或缓解最受欢迎的方法 例如冲击和杀伤方法，广泛中和抗体，嵌合抗原受体和治疗性 疫苗都需要对潜在病毒的某种形式的重新激活。 但是，结核病是可能影响病毒储层及其对潜伏期的反应的重要因素 在HIV治疗研究的背景下，逆转剂（LRAS）并未受到太多关注。超过三分之一的艾滋病毒 患者感染了结核病。结核病，包括潜在结核病感染（LTBI），会产生刺激的抗原 T细胞，可能导致增殖并改变储层对LRA的反应。持续的刺激 也可能导致T细胞耗尽。 我们正在处理以下假设：共同感染患者血液中的结核病抗原刺激T细胞到 增加储层的大小，并改变CD8+和CD8+ T细胞的响应。我们将调查此事 以下特定目的的假设： 目标1：确定HIV和HIV/LTB患者之间T细胞反应的差异。我们假设这是 受感染的患者，CD4+ T细胞对LRA的反应降低，CD8+ T细胞将减少杀伤 刺激的能力。首先，我们将比较病毒学中静止的T细胞的基线激活状态 用HIV或HIV/LTBI抑制患者（VL <50份）。其次，我们将刺激CD4+和CD8+ 每组的T细胞生产相关细胞因子以及激活和精疲力尽的表达 标记。第三，我们将从患者中分离静息T细胞，并用不同的LRA刺激它们。第四，我们 将确定共同感染患者的CD8+ T细胞的能力杀死重新激活的CD4+ T细胞表达 HIV-1抗原。 AIM 2：仅在HIV中确定HIV水库的大小和HIV/LTB共感染的患者。我们假设 由于持续的刺激，共感染的患者将具有较大的储层大小，从而导致进一步的CD4+ T细胞播种或克隆膨胀。我们将从我们的队列中招募仅75名HIV患者和75名HIV-TB患者 每毫升的病毒载荷小于50份超过2年。我们将分离静息T细胞以测量 使用IPDA测定法的储层，该测定法仅测量具有产生病毒潜力的完整原病毒。 该项目将提供严重缺失的知识，并了解患者中T细胞如何与患者共同感染 结核病响应潜伏期逆转剂，并指示这些患者的艾滋病毒水库的大小。 获得的信息对于在共同感染的患者中计划HIV治疗研究至关重要。