Immunologic And Virologic Approaches To HIV-1 Therapeutics

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组合抗逆转录病毒疗法;如何在持续抗逆转录病毒疗法的框架内整合基于免疫的疗法;如何确定开始抗逆转录病毒策略的最佳时间，以保持和重建免疫功能，同时最大限度地减少长期抗逆转录病毒毒性，进行性HIV感染在服用和不服用抗逆转录病毒药物时产生不良后果的预测因素是什么？ 当前抗逆转录病毒策略中最大的未满足的目标之一是开发一种成功的手段，该手段耗尽甚至可能最终根除即使在血浆病毒水平被抑制在常规检测方法的限度以下之后仍保留在宿主淋巴细胞、巨噬细胞和其他细胞储库中的潜伏病毒储库。如果能够在不造成不可接受的药物毒性水平和/或涉及无法轻易广泛适应更大规模的艾滋病毒感染者群体的激进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宿主的潜伏病毒，一旦抗逆转录病毒治疗停止，潜伏病毒就不会反弹。 在这方面，我们正在协助其他NIAID和NCI研究人员计划和初步临床前测试的一种新的“免疫毒素”，单克隆抗体连接假单胞菌外毒素，可能有直接的抗病毒活性凭借其对艾滋病毒感染的细胞的亲和力。这种免疫毒素的潜在价值在于，与靶向病毒复制周期的各个阶段的常规抗逆转录病毒药物不同，体内和动物研究表明，这种药剂选择性地破坏携带病毒并在细胞表面表达病毒抗原的宿主细胞。一旦被批准用于人体试验，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剂添加到有效的HAART中是否进一步耗尽潜伏病毒库到单独使用后一种药剂无法达到的程度。 在美国国立卫生研究院临床中心，我们也是“START”研究（抗逆转录病毒治疗的战略时机）的试验和子研究中心之一，旨在确定早期引入ART是否能使先前未经治疗的患者获得更好的临床结果。目前卫生与公众服务部的抗逆转录病毒指南建议对CD 4细胞计数为500个细胞/L或更少的HIV感染者开始HAART治疗。然而，这些建议存在争议，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试验是一项大型多国试验，招募了CD 4细胞计数高于500个细胞/L的抗逆转录病毒初治HIV感染者，并随机分配他们立即开始HAART或延迟HAART的开始，直到CD 4细胞计数福尔斯降至350个细胞/L以下。这项为期4-5年的试验的主要目的是比较两组由于进行性HIV感染或HAART本身毒性引起的不良后果的累积发生率。 最后，我们还继续努力，通过外联活动，包括与当地诊所建立密切关系，为医疗服务不足的人口提供更多的临床试验机会。

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 and substudy 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.