Viral and Immune Dynamics of Rebound Viremia after VRC01 Administration

 描述(申请人提供)：最近发现的一代广泛中和的单抗(BNAbs)为HIV-1的治疗、预防和治愈带来了巨大的希望。虽然早期的bNAbs在人体试验中未能抑制反弹病毒血症，但最近的动物研究表明，被动注射这些较新的bNAbs可以防止HIV-1感染，并有效地抑制反弹病毒血症。此外，一项对感染SHIV病毒的猕猴的研究表明，给予bNAb可能会增强HIV特异的T细胞反应，并降低跨组织间隔的前病毒DNA水平。这些发现提高了人们对bNAbs在艾滋病毒治疗策略中的潜在作用的热情，并突显了这种来自小鼠和猕猴研究的令人兴奋的数据在人类身上得到验证的必要性。艾滋病临床试验小组研究A5340是第一个在分析治疗中断(ATI)的情况下评估bNAb抑制反弹病毒血症能力的人类临床试验。A5340将测试VRC01在抗逆转录病毒治疗中断时抑制反弹病毒血症的能力。VRC01是一种针对HIV-1的广泛中和抗体，其靶向是保守的CD4结合位点，以广泛中和跨分支的HIV-1病毒。在这一应用中，我们建议利用这一重要的临床试验来解决补充问题，即bNAbs如何调节宿主免疫反应，并改变ATI后反弹的病毒动力学。同时，我们将阐明目前尚不清楚的基本病毒和 基线时未注射bNAb的反跳性病毒血症的免疫学机制，作为一个参照物。我们的主要假设是，VRC01给药会增强宿主的免疫反应，并改变治疗中断期间病毒反弹的动力学。为了验证这一假设，我们将对A5340中未识别的临床样本和先前进行的ATI临床试验进行一系列整合的病毒和T细胞研究。具体地说，我们将测试VRC01如何影响(I)反弹病毒的克隆性和中和敏感性，以及(Ii)T细胞反应的时间、功能和预测能力。总之，这些研究将描述反跳性病毒血症的基线病毒动力学和免疫反应，以及VRC01免疫治疗如何改变它们。此外，结果可能确定具有临床价值的生物标志物和预测病毒反弹的分析。我们预计这些研究将与A5340的结果协同作用，更好地表征VRC01的免疫调节作用及其在根除HIV-1中的潜在作用，并可能对在HIV治疗、预防和治疗议程中使用bNAbs产生广泛影响。

 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.