Specific killing of latently HIV-1-infected cells after provirus reactivation

原病毒重新激活后特异性杀死潜伏 HIV-1 感染的细胞

基本信息

批准号：
9276563
负责人：
Qigui Q Yu
金额：
$ 38.64万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-01-01 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9276563
关键词：
Anti-Retroviral Agents Antibodies Antibody Response Autologous Biological Assay CD4 Positive T Lymphocytes Cell Line Cells Chronic Complement Complement Activation Cytolysis Detection Diagnostic Failure Gene Expression Goals Grant HIV-1 Highly Active Antiretroviral Therapy Human Immune response Immunity Impairment In Vitro Individual Infection Interleukin-7 Measurable Mediating Medical Memory Modeling Morbidity - disease rate Patients Pharmaceutical Preparations Phase Production Proliferating Proviruses Public Health Reporting Research Residual state Rest Surface T-Lymphocyte Testing Vaccines Valproic Acid Viral Viral Cytopathogenic Effect Viral Proteins Viremia Virion Virus Vorinostat antiretroviral therapy cell type effective therapy experience global health improved in vivo inhibitor/antagonist innovation killings member mortality novel strategies pandemic disease prostratin purge

项目摘要

PROJECT SUMMARY/ABSTRACT The HIV-1 pandemic has claimed over 20 million lives, with 38.6 million people worldwide currently infected, and will continue to be a significant global health problem as there is no vaccine available. Currently, the only effective treatment available to HIV-1 infection is HAART (highly active antiretroviral therapy), which has led to a profound reduction in HIV-1-related morbidity and mortality. However, HAART fails to eliminate the virus in vivo, mainly due to the persistent existence of long-lived latently-infected cells harboring replication-competent proviruses. Efforts to purge these infected cells have focused on reactivation of the proviruses. It is presumed that these infected cells will be killed after reactivation of virus gene expression by viral cytopathic effects (CPEs), host immune responses or both. Several stimulants including IL-7, valproic acid (VPA), suberoylanilide hydroxamic acid (SAHA) and prostratin have been explored to force activation of proviruses in latently-infected resting CD4+ T cells that constitute the major reservoir of HIV-1 in vivo. However, treatment with IL-7 or VPA in patients on HAART has failed to reduce HIV-1 latency, suggesting that these agents alone are not sufficient to induce killing of latently-infected cells. We propose to develop an “activation-killing” approach by combining provirus stimulants with an agent that is able to allow anti-HIV-1 immunity naturally mounted in patients during HIV-1 infection to specifically kill latently-infected cells after provirus reactivation. Studies have shown that both HIV-1-infected cells and virions use their surface regulators of complement activation (RCA) to resist antibody- dependent complement-mediated lysis (ADCML), which explains why vigorous and sustained anti-HIV-1 envelope (Env) antibody (Ab) responses in almost all infected individuals fail to control HIV-1 infection. We and others have reported that blocking human CD59 (hCD59), a key member of RCA, renders both HIV-1-infected cells and virions sensitive to ADCML. We therefore hypothesize that addition of an hCD59 inhibitor to SAHA, prostratin or both will enable anti-HIV-1 Env Abs naturally present in HIV-1-infected individuals to trigger ADCML of latently-infected T cells after provirus reactivation. The provirus stimulants will activate proviruses to express viral proteins on the surface of latently-infected cells that will be killed by ADCML if hCD59 is inhibited. We will use the human T cell line ACH2, a well-characterized model of HIV-1-latency, to develop such an approach (Aim 1, R21 Phase). We will verify whether the approach is able to trigger ADCML of the primary CD4+ T cells latently infected with HIV-1 in vitro (Aim 2, R33 Phase). We will then determine if this approach can allow anti-HIV-1 Abs naturally present in the sera of infected patients to trigger autologous ADCML of their own latently-infected resting CD4+ T cells (Aim 3, R33 Phase). Our project is innovative and significant because we aim to develop a novel approach for purging the persistent reservoir of HIV-1 in patients on HAART. This approach may simultaneously target various latently infected cells and residual viremia, potentially leading to a broader impact and improved efficacy against the various persistent HIV-1 reservoirs.

项目概要/摘要 HIV-1 大流行已夺去了超过 2000 万人的生命，目前全球有 3860 万人受到感染，并将继续成为一个重大的全球健康问题，因为目前没有可用的疫苗。针对 HIV-1 感染的有效治疗方法是 HAART（高效抗逆转录病毒疗法），这导致 HIV-1 相关发病率和死亡率普遍降低，但 HAART 未能消除该病毒。体内，主要是由于具有复制能力的长寿命潜伏感染细胞的持续存在据推测，清除这些受感染细胞的努力集中在原病毒的重新激活上。通过病毒细胞病变效应重新激活病毒基因表达后，这些受感染的细胞将被杀死 (CPE)、宿主免疫反应或两者兼而有之。几种兴奋剂，包括 IL-7、丙戊酸 (VPA)、辛二酰苯胺。异羟肟酸（SAHA）和前列腺素已被探索用于强制激活潜伏感染者中的原病毒静息 CD4+ T 细胞构成体内 HIV-1 的主要储存库，但用 IL-7 或 VPA 治疗。接受 HAART 治疗的患者未能减少 HIV-1 潜伏期，这表明单靠这些药物不足以我们建议通过结合来开发一种“激活杀伤”方法。前病毒兴奋剂含有一种能够使患者在治疗期间自然产生抗 HIV-1 免疫力的药物 HIV-1感染后原病毒重新激活可特异性杀死潜伏感染细胞。 HIV-1 感染的细胞和病毒颗粒利用其补体激活表面调节因子 (RCA) 来抵抗抗体依赖补体介导的裂解 (ADCML)，这解释了为什么强力和持续的抗 HIV-1 几乎所有感染者的包膜 (Env) 抗体 (Ab) 反应都无法控制 HIV-1 感染。其他人报告说，阻断人类 CD59 (hCD59)（RCA 的关键成员）会导致 HIV-1 感染因此，我们捕捉到了在 SAHA 中添加 hCD59 抑制剂的情况。前列腺素或两者都会使 HIV-1 感染者体内天然存在的抗 HIV-1 包膜抗体能够触发原病毒重新激活后晚期感染的 T 细胞的 ADCML。原病毒兴奋剂将激活原病毒。在潜伏感染细胞表面表达病毒蛋白，如果 hCD59 受到抑制，这些病毒蛋白将被 ADCML 杀死。我们将使用人类 T 细胞系 ACH2（一种经过充分表征的 HIV-1 潜伏期模型）来开发这样的方法（目标 1，R21 阶段）我们将验证该方法是否能够触发主设备的 ADCML。 CD4+ T 细胞在体外潜伏感染 HIV-1（目标 2，R33 阶段），然后我们将确定这种方法是否有效。可以让感染患者血清中天然存在的抗 HIV-1 抗体触发其自体 ADCML 我们的项目是创新且意义重大的。因为我们的目标是开发一种新方法来清除患者体内持续存在的 HIV-1 病毒这种方法可以同时针对各种潜伏感染细胞和残留病毒血症，可能会产生更广泛的影响并提高针对各种持久性 HIV-1 病毒库的功效。