Viral and Immune Dynamics of Rebound Viremia after VRC01 Administration

VRC01给药后病毒血症反弹的病毒和免疫动力学

• 批准号: 8923889
• 负责人: Katharine June Bar
• 金额: $ 24万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-15 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8923889
• 关键词: AIDS clinical trial group; Address; Adult; Affect; Animals; Antibody Response; Antibody Therapy; Binding Sites; Biological Assay; Biological Markers; CD8B1 gene; Cells; Clinical; Clinical Trials; Clonality; Conduct Clinical Trials; DNA; Data; Development; Dose; Drug Kinetics; Event; Flow Cytometry; Funding; Future; Generations; Goals; HIV; HIV-1; Human; Immune; Immune response; Immunotherapy; Infusion procedures; Interruption; Link; Macaca; Measures; Mus; Pattern; Phase; Plasma; Population; Prevention; Preventive; Property; Relapse; Resistance; Role; Safety; Sampling; Series; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Time; Tissues; Viral; Viremia; Virus; Virus Replication; antiretroviral therapy; design; exhaustion; human monoclonal antibodies; improved; killings; neutralizing antibody; neutralizing monoclonal antibodies; next generation; open label; pressure; prevent; public health relevance; simian human immunodeficiency virus

 DESCRIPTION (provided by applicant): The recently discovered generation of broadly neutralizing monoclonal antibodies (bNAbs) hold great promise for HIV-1 treatment, prevention and cure. While earlier bNAbs failed to suppress rebound viremia in human trials, recent animal studies have shown that passive infusion of these newer bNAbs can prevent HIV-1 acquisition and potently suppress rebound viremia. Further, a study in SHIV-infected macaques suggested that bNAb administration may enhance HIV-specific T cell responses and reduce proviral DNA levels across tissue compartments. These findings raise enthusiasm for bNAbs' potential role in HIV cure strategies and highlight the need for this exciting data from murine and macaque studies to be validated in humans. The AIDS Clinical Trials Group study A5340 is the first human clinical trial to assess the ability of a bNAb to suppress rebound viremia in the context of an analytical treatment interruption (ATI). A5340 will test the ability of VRC01, a broadly neutralizing antibody to HIV-1 that targets the conserved CD4 binding site to broadly neutralize HIV-1 viruses across clades, to suppress rebound viremia upon interruption of antiretroviral therapy. In this application, we propose to capitalize on this important clinical trial to address complementary questions of how bNAbs modulate host immune responses and alter the viral dynamics of rebound after ATI. In parallel, we will elucidate the currently unclear basic viral and immunological mechanisms of rebound viremia at baseline without bNAb administration, to serve as a comparator. Our overarching hypothesis is that VRC01 administration will enhance the host immune responses and alter the viral dynamics of rebound during treatment interruption. To test this hypothesis, we will perform a series of integrated viral and T cell studes on de-identified clinical samples from A5340 and previously conducted clinical trials of ATI. Specifically, we will test how VRC01 affects (i) the clonality and neutralization sensitivity of rebound viruses and (ii) the timing, functionality and predictive capacity of T cell responses. Together, these studies will characterize the baseline viral dynamics and immune responses of rebound viremia and how immunotherapy with VRC01 alters them. Further, results may identify clinically valuable biomarkers and assays that are predictive of viral rebound. We expect these studies will synergize with the results of A5340 to better characterize the immunomodulatory effects of VRC01 and its potential role in HIV-1 eradication and potentially have broad implications for use of bNAbs across the HIV treatment, prevention and cure agendas.

 描述（由适用提供）：最近发现的广泛中和单克隆抗体（BNABS）的产生对HIV-1治疗，预防和治疗具有巨大的希望。虽然早期的BNAB在人类试验中未能抑制反弹病毒血症，但最近的动物研究表明，对这些较新的BNAB的被动输注可以防止HIV-1获取，并可能抑制反弹病毒血症。此外，一项对SHIV感染猕猴的研究表明，BNAB给药可以增强HIV特异性T细胞反应并降低整个组织室中的DNA水平。这些发现对BNABS在艾滋病毒治疗策略中的潜在作用产生了热情，并强调了对鼠类和猕猴研究中对人类进行验证的令人兴奋的数据的需求。 AIDS临床试验小组研究A5340是第一个评估BNAB抑制反弹病毒血症能力的人类临床试验（ATI）。 A5340将测试VRC01的能力，VRC01是一种靶向HIV-1的广泛中和抗体，该抗体靶向已配置的CD4结合位点，以在整个进化枝中广泛中和HIV-1病毒，从而在中断抗逆转录病毒治疗后抑制反弹病毒血症。在此应用程序中，我们建议利用这项重要的临床试验，以解决BNABS如何调节宿主免疫反应并改变ATI后反弹的病毒动态的完整问题。同时，我们将阐明当前不清楚的基本病毒和 基线时反弹病毒血症的免疫学机制无BNAB给予比较。我们的总体假设是，VRC01给药将增强宿主免疫回报并改变治疗中断期间反弹的病毒动力学。为了检验这一假设，我们将对来自A5340的去识别的临床样本进行一系列集成病毒和T细胞研究，并以前进行了ATI的临床试验。具体而言，我们将测试VRC01如何影响回弹病毒的克隆性和神经元化敏感性以及（ii）T细胞反应的时间，功能和预测能力。总之，这些研究将表征基线病毒动力学和反弹病毒血症的免疫疗法以及VRC01免疫疗法如何改变它们。此外，结果可能会确定临床上有价值的生物标志物和可预测病毒反弹的测定法。我们预计这些研究将与A5340的结果协同作用，以更好地表征VRC01的免疫调节作用及其在HIV-1消除HIV-1中的潜在作用，并有可能对在HIV，预防和治疗议程中使用BNAB的使用具有广泛的意义。