Immunologic And Virologic Approaches To HIV-1 Therapeutics

HIV-1 治疗的免疫学和病毒学方法

• 批准号: 8148402
• 负责人: Richard Davey
• 金额: $ 203.64万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8148402
• 关键词: Address; Affinity; Data; Detection; Drug toxicity; Enrollment; HIV-1; Immunologics; Improve Access; Latent Virus; National Institute of Allergy and Infectious Disease; Pharmaceutical Preparations; Preclinical Testing; Randomized; Therapeutic; immune function; in vivo

Our clinical research continues to address several important aspects of the following questions: how to optimally use and administer multi-class combination anti-retroviral therapy; how to integrate immune based therapies within a framework of ongoing antiretroviral therapy; how to determine the optimal time for initiation of antiretroviral strategy in order to preserve and reconstitute immune function while at the same time minimizing long-term antiretroviral toxicities, and what are some of the predictive factors for the development of adverse consequences of progressive HIV infection both on and off antiretroviral medications. One of the greatest unmet goals in current antiretroviral strategies is to develop a successful means of depleting, perhaps ultimately even eradicating, the reservoir of latent virus that remains in host lymphocytes, macrophages, and other cellular reservoirs even after levels of plasma virus are suppressed below the limits of conventional detection methods. If such eradication could be achieved without inflicting unacceptable levels of drug toxicity and/or involving radical therapies that could not easily be broadly adapted to the larger community of HIV-infected individuals, it is conceivable that a combination treatment approach could be developed to purge HIV-infected hosts of latent virus that would not rebound once antiretroviral therapy was discontinued. In this regard, we are assisting other NIAID and NCI investigators in the planning and initial preclinical testing of a novel "immuno-toxin", a monoclonal antibody linked with pseudomonas exotoxin, that may have direct antiviral activity by virtue of its affinity for HIV-infected cells. The potential value of this immunotoxin is that, unlike conventional antiretroviral medications that target various stages of the viral replication cycle, in vivo and animal studies have shown that this agent selectively destroys host cells harboring the virus and expressing viral antigen on the cell surface. Once approved for human testing, the goal of upcoming clinical trials will be to determine safety as well as to determine whether addition of this agent to effective HAART further depletes the latent viral reservoir to a degree not achievable by the latter agents alone. At the NIH Clinical Center we are also fully operational as one of the trial sites for the "START" study (Strategic Timing of AntiRetroviral Treatment) aimed at determining whether early introduction of ART in previously-untreated patients translates into better clinical outcomes. Current Department of Health and Human Services Antiretroviral Guidelines recommend the initiation of HAART for HIV-infected individuals with CD4 cell counts of 500 cells/L or less. However, those recommendations are controversial in that they are based upon the outcomes of large observational trials and not data from a randomized clinical trial. In order to address this question more rigorously, the START trial is a large multi-national trial enrolling antiretroviral-naive HIV-infected individuals with CD4 cell counts above 500 cells/L and randomly assigning them either to begin HAART immediately or to delay the start of HAART until the CD4 cell count falls below 350 cells/L. The primary goal of this 4-5 year trial will be to compare the two arms in terms of the cumulative incidence of adverse consequences ascribable either to progressive HIV infection or to the toxicities of HAART itself. Finally, we also continue our efforts to improve access to clinical trials by local minority populations through an outreach that includes a close relationship with local clinics for medically under-served populations.

我们的临床研究继续解决以下问题的几个重要方面：如何最佳地使用和管理多类联合抗逆转录病毒疗法；如何将基于免疫的疗法整合到正在进行的抗逆转录病毒疗法的框架内；如何确定开始抗逆转录病毒策略的最佳时间，以保留和重建免疫功能，同时最大限度地减少长期抗逆转录病毒毒性，以及进行性艾滋病毒感染产生不良后果的一些预测因素是什么断断续续服用抗逆转录病毒药物。 当前抗逆转录病毒策略中最大的未实现目标之一是开发一种成功的方法，即使在血浆病毒水平被抑制到低于以下水平后，也能成功地耗尽、甚至最终根除残留在宿主淋巴细胞、巨噬细胞和其他细胞病毒库中的潜伏病毒库。传统检测方法的局限性。如果可以在不造成不可接受的药物毒性水平和/或涉及不易广泛适应更广泛的艾滋病毒感染者群体的根本疗法的情况下实现这种根除，那么可以想象，可以开发一种联合治疗方法来清除艾滋病毒-感染潜伏病毒的宿主，一旦停止抗逆转录病毒治疗就不会反弹。 在这方面，我们正在协助其他 NIAID 和 NCI 研究人员规划和初步临床前测试一种新型“免疫毒素”，这是一种与假单胞菌外毒素相关的单克隆抗体，由于其对 HIV 的亲和力，可能具有直接抗病毒活性。被感染的细胞。这种免疫毒素的潜在价值在于，与针对病毒复制周期各个阶段的传统抗逆转录病毒药物不同，体内和动物研究表明，该药物选择性破坏含有病毒并在细胞表面表达病毒抗原的宿主细胞。一旦批准用于人体测试，即将进行的临床试验的目标将是确定安全性以及确定将该药物添加到有效的HAART中是否会进一步耗尽潜伏病毒库，达到单独使用后者药物无法达到的程度。 在 NIH 临床中心，我们也作为“START”研究（抗逆转录病毒治疗的战略时机）的试验地点之一全面投入运营，该研究旨在确定对先前未经治疗的患者早期引入 ART 是否会转化为更好的临床结果。当前的卫生与公共服务部抗逆转录病毒指南建议对 CD4 细胞计数等于或低于 500 个细胞/L 的 HIV 感染者启动 HAART。然而，这些建议是有争议的，因为它们是基于大型观察性试验的结果，而不是随机临床试验的数据。为了更严格地解决这个问题，START试验是一项大型跨国试验，招募CD4细胞计数超过500个细胞/L的未接受过抗逆转录病毒治疗的HIV感染者，并随机分配他们立即开始HAART或推迟开始HAART 直至 CD4 细胞计数降至 350 个细胞/L 以下。这项为期 4-5 年的试验的主要目标是比较两组不良后果的累积发生率，这些不良后果可归因于进行性 HIV 感染或 HAART 本身的毒性。 最后，我们还继续努力，通过与当地诊所为医疗服务不足的人群建立密切关系等外展活动，改善当地少数群体获得临床试验的机会。