IMPACT OF TUBERCULOSIS ON THE HIV RESERVOIR

项目总结 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 解药。患者必须承诺每天服药，并应对副作用、不可持续的费用和药物 抵抗。HIV治愈的主要障碍是静止的CD4T细胞储存库中的持久性前病毒 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 如休克和杀死方法、广谱中和抗体、嵌合抗原受体和治疗性 疫苗都需要以某种形式重新激活潜伏的前病毒。 然而，结核病，一个可能影响病毒库及其对潜伏期的反应的重要因素 在HIV治愈研究中，逆转药物(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，包括潜伏的结核病感染(LTBI)，会产生抗原，刺激 T细胞，这可能导致增殖，并改变储存库对LRAs的反应。持续刺激 也可能导致T细胞耗尽。 我们正在研究一种假设，即合并感染患者血液中的结核病抗原刺激T细胞 增加储存库的大小，改变CD8和CD8T细胞的反应。我们将对此进行调查 假设有以下具体目的： 目的1：确定HIV和HIV/LTB患者T细胞应答的差异。我们假设在联合- 感染患者，CD4T细胞对LRA的反应性降低，CD8T细胞的杀伤作用降低 在刺激下的能力。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 受抑制的HIV或HIV/LTBI患者(每毫升50个拷贝)。二是刺激外周血中的CD4、CD8 各组T细胞对相关细胞因子的产生及表达的激活和耗竭 记号笔。第三，我们将分离患者的静息T细胞，并用不同的LRA刺激它们。第四，我们 将确定来自混合感染患者的CD8 T细胞杀伤重新激活的CD4T细胞的能力 HIV-1抗原。 目的2：确定HIV单独感染者和HIV/LTB混合感染者的HIV储备库的大小。我们假设 由于持续的刺激导致进一步的CD4，合并感染的患者将有更大的储存库大小 T细胞接种或克隆性扩增。我们将从我们的队列中招募75名仅感染艾滋病毒的患者和75名感染艾滋病毒的结核病患者。 病毒载量为每毫升50个拷贝，持续两年多。我们将分离静息T细胞以测量其大小 使用IPDA检测的蓄水池只测量有可能产生病毒的完整前病毒。 该项目将提供严重缺乏的知识和理解的T细胞如何在患者的共同感染 结核病对潜伏期反转剂有反应，并对这些患者的艾滋病毒宿主的大小做出指示。 所获得的信息将对规划针对混合感染患者的艾滋病毒治愈研究至关重要。

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.