Novel strategies for eliminating HIV reservoirs in lymphoid tissues

 描述(申请人提供)：高效的抗逆转录病毒疗法大大减少了HIV-1的复制和病毒血症，使其低于临床检测的限度，并减缓了向艾滋病的进展速度。然而，尽管长期抗逆转录病毒治疗(ART)，残留的病毒库仍然以整合和转录沉默前病毒的形式持续潜伏状态， 导致艾滋病毒-1感染者在停止抗逆转录病毒治疗后终身感染和病毒反弹。HIV感染治疗的主要障碍是如何清除隐窝组织中持续和潜伏的HIV感染细胞，特别是在有组织的淋巴组织的生发中心(GC)。通过我们的新型调控治疗策略，我们将逆转潜伏的病毒感染细胞，阻止GC中新储存库的补充，同时在猕猴体内引发抑制ART的次要IgM反应。为了实现这一目标，我们将依次给予ART，结合PKC激活剂前列腺素(PRO)和免疫调节mTOR抑制剂雷帕霉素(RAPA)，然后是抗HIV-1包膜抗体-药物结合物(ADC)，以消除残留的感染细胞。我们推测，这一全面的“休克并杀死”策略还将导致CTL功能的恢复和受感染宿主抗体反应的改善，这两者结合在一起，可能导致对患者的HIV进行灭菌，或者至少是“功能性”治愈。这一治疗策略的可行性、安全性和有效性将在高度相关的恒河猴HIV感染的SIV模型中进行测试。我们的长期目标是为艾滋病毒感染者开发一种绝育疗法，这些研究将为这一雄心勃勃的目标的可行性和实用性提供关键信息。

 DESCRIPTION (provided by applicant): Highly active antiretroviral therapy has dramatically reduced HIV-1 replication and viremia below the clinical limit of detection, and slows the rate of progression to AIDS. However, residual viral reservoirs still persist in a latent state in the formof integrated and transcriptionally silent proviruses, despite long-term antiretroviral therapy (ART), resulting in lifelong infection and viral rebounds in HIV-1-infected individuals upon ART cessation. The major obstacle to a cure for HIV infection is how to purge the persistently and latently HIV- infected cells in recessed tissues, especially in germinal centers (GC) of organized lymphoid tissues. With our novel-modulatory therapeutic strategy, we will reverse latently virus-infected cells, block replenishment of new reservoirs in GC, while simultaneously eliciting subdominant IgM responses in macaques on suppressive ART. To accomplish this we will sequentially administer ART, combined with the PKC activator prostratin (PRO) and immunomodulatory mTOR inhibitor rapamycin (RAPA) followed by anti-HIV-1 envelope antibody-drug conjugates (ADC) to eliminate residual infected cells. We hypothesize this comprehensive "shock and kill" strategy will also result in restoration of CTL function and improved antibody responses in infected hosts, which combined, may result in a sterilizing, or at least a "functional" cure for HIV in patients. The feasibility, safety, and efficacy of this cure strategy will be tested in the highly relevant SHIV model of HIV infection in rhesus macaques. Our long-term goal is to develop a sterilizing cure for HIV infected patients, and these studies will provide critical information as to the feasibility and practicality of this ambitious goal.