Tropism, Susceptibility and Resistance Deteminants

迫切需要针对病毒复制周期的不同阶段的新的艾滋病毒-1疗法，以抗击日益普遍的多药耐药病毒，并减少治疗毒性。趋化因子受体CCR5通过与HIV-1的主要受体CD4共同作用，作为HIV-1进入的关键门户。CCR5在病毒传播和发病机制中发挥核心作用，因此是HIV-1新疗法的一个有吸引力的靶点。PRO 140是一种独特的人源化CCR5单抗(MAb)，提供了一种新的治疗方案。与正在开发的小分子CCR5拮抗剂不同，PRO 140广泛而有效地抑制CCR5介导的HIV-1进入，而不会阻断或以其他方式失调CCR5的自然活动。此外，PRO 140在健康志愿者身上进行的1a期临床试验中显示出良好的耐受性和药代动力学特征。PRO 140与小分子的明显区别在于它缺乏CCR5拮抗作用、病毒耐药模式不重叠、抗病毒协同作用、出色的耐受性以及可能不频繁(例如，每月)给药。因此，PRO 140可能会定义一个独特的CCR5抑制剂亚类，我们将在项目1中探索这个问题。没有CCR5抑制剂和针对任何靶点的mAb被批准用于HIV-1治疗，这进一步强调了这种治疗方法的高度创新性。在项目3中，我们将利用新的表型和基因分型技术来检测病毒的嗜性、对PRO 140的敏感性和耐药性。初步研究将使用从6000个成员的病毒库中选择的广泛的病毒小组，重点放在潜在的关键控制参数上，探索PR140易感性的自然变异。该项目的一个主要重点是在项目2的临床试验中监测接受PRO 140治疗的患者的辅受体使用情况和PRO 140敏感性。在这一能力中，我们将识别存在纯R5病毒的合格研究患者，我们将监测研究参与者的辅受体使用情况或PRO 140敏感性的任何变化。我们将检查是否有任何抗药性变异代表先前存在的次要物种的副产品或 是对治疗作出反应的序列进化的结果。这些变异体将在体外进行分析，以确定它们的分子机制和抗药性的遗传决定因素，对HIV-1进入和酶抑制剂的交叉抗药性模式，以及内在的融合能力。我们的实验室研究将与摩尔博士合作进行(项目1)，我们将使用不同的研究方法解决一系列互补的问题。项目3对于开展项目2的首例艾滋病毒临床研究以及IPCP通过一系列综合的临床前和临床概念验证研究以最佳方式将PRO 140从创新的治疗概念转化为有前途的新的研究试剂的总体目标来说是至关重要的。

There is an urgent need for new HIV-1 therapies targeting different steps of the viral replicative cycle to combat the growing prevalence of multidrug-resistant viruses and to reduce treatment toxicities. The chemokine receptor CCR5 serves as a critical portal of HIV-1 entry by acting as a fusion coreceptor in conjunction with CD4, the primary receptor for HIV-1. CCR5 plays a central role in virus transmission and pathogenesis, and therefore represents an attractive target for new HIV-1 therapies. PRO 140 is a unique humanized CCR5 monoclonal antibody (mAb) that offers a novel therapeutic profile. Unlike small-molecule CCR5 antagonists under development, PRO 140 broadly and potently inhibits CCR5-mediated HIV-1 entry without blocking or otherwise dysregulating the natural activities of CCR5. In addition, PRO 140 has demonstrated favorable tolerability and pharmacokinetic profiles in an ongoing Phase la clinical trial in healthy volunteers. PRO 140 is clearly differentiated from small molecules in terms of its lack of CCR5 antagonism, nonoverlapping patterns of viral resistance, antiviral synergy, excellent tolerability profile, and potential for infrequent (e.g., monthly) dosing. PRO 140 may therefore define a unique CCR5 inhibitor subclass, an issue that we will explore in Project 1. The highly innovative nature of this therapeutic approach is further underscored by the fact that no CCR5 inhibitor and no mAb to any target have been approved for HIV-1 therapy. In Project 3, we will utilize novel phenotypic and genotypic technologies to examine viral tropism, susceptibility and resistance to PRO 140. Initial studies will explore the natural variation in PRO 140 susceptibility using a broad panel of viruses selected from the 6000-member ViroLogic library with an emphasis on potential key controlling parameters. A primary focus of this Project is to monitor coreceptor usage and PRO 140 susceptibility in patients treated with PRO 140 in the clinical trials of Project 2. In this capacity, we will identify eligible study patients who present with pure R5 viruses, and we will monitor study participants for any change in coreceptor usage or PRO 140 susceptibility. We will examine whether any resistant variants represent outgrowth of pre-existing minor species or are the result of sequence evolution in response to therapy. The variants will be analyzed in vitro to determine their molecular mechanisms and genetic determinants of resistance, patterns of cross-resistance to HIV-1 entry and enzyme inhibitors, and intrinsic fusogenicity. Our laboratory research will be carried out in collaboration with Dr. Moore (Project 1), and we will address a complementary set of issues using distinct research methodologies. Project 3 is essential to the conduct of the first-in-HIV clinical studies of Project 2 and to the overall IPCP goal of optimally translating PRO 140 from an innovative treatment concept into a promising new investigational agent via an integrated series of preclinical and clinical proof-of-concept studies.