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.

项目概要 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 治愈。患者必须每天服药并应对副作用、不可持续的成本和药物 反抗。 HIV 治愈的主要障碍是静息 CD4+ T 细胞库中持续存在的原病毒， 在适当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 例如休克和杀伤方法、广泛中和抗体、嵌合抗原受体和治疗 疫苗都需要某种形式的潜伏原病毒重新激活。 然而，结核病是可能影响病毒库及其对潜伏期反应的重要因素 逆转剂（LRAs）在艾滋病毒治疗研究中并未受到太多关注。超过三分之一的艾滋病毒 患者感染了结核病。结核病，包括潜伏性结核感染 (LTBI)，产生的抗原可刺激 T 细胞，可能导致增殖并改变储存库对 LRA 的反应。持续刺激 也可能导致 T 细胞耗竭。 我们正在研究这样的假设：共感染患者血液中的结核抗原会刺激 T 细胞 增加储存库的大小并改变 CD8+ 和 CD8+ T 细胞的反应。我们将对此进行调查 具有以下具体目标的假设： 目标 1：确定 HIV 和 HIV/LTB 患者之间 T 细胞反应的差异。我们假设在共同 受感染的患者，CD4+ T 细胞对 LRA 的反应会减少，CD8+ T 细胞的杀伤力也会减少 受刺激后的能力。首先，我们将从病毒学角度比较静息 T 细胞的基线激活状态 抑制的 HIV 或 HIV/LTBI 患者（VL <50 拷贝/毫升）。其次，我们会刺激CD4+和CD8+ 各组T细胞产生相关细胞因子及表达的激活和耗竭 标记。第三，我们将从患者体内分离出静息 T 细胞，并用不同的 LRA 刺激它们。第四，我们 将确定来自共感染患者的 CD8+ T 细胞杀死表达的重新激活的 CD4+ T 细胞的能力 HIV-1 抗原。 目标 2：确定仅 HIV 感染和 HIV/LTB 合并感染患者中 HIV 储存库的大小。我们假设 由于持续刺激导致进一步 CD4+，合并感染的患者将具有更大的储库尺寸 T 细胞接种或克隆扩增。我们将从我们的队列中招募 75 名仅感染 HIV 的患者和 75 名 HIV-TB 患者 病毒载量<50拷贝/毫升持续超过2年。我们将分离静息 T 细胞来测量 使用 IPDA 检测来检测病毒库，该检测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和理解，了解患者体内的 T 细胞如何同时感染 结核病对潜伏期逆转剂有反应，并表明这些患者体内艾滋病毒储存库的大小。 获得的信息对于规划共同感染患者的艾滋病毒治疗研究至关重要。