Impact of CCR5 Blockade in HIV+ Kidney Transplant Recipients

描述（由申请人提供）：尽管在过去的25年里免疫抑制方案得到了相当大的改进，肾移植后急性排斥反应的发生率也有所下降，但长期移植结果并没有以同样的速度改善，而且仍然停滞不前。此外，在开发新的免疫抑制策略以减少急性和慢性损伤方面相对缺乏。马拉维洛克是一种CCR5抑制剂，可能在调节移植后的免疫反应中具有新的作用。测试其对同种免疫反应影响的理想环境是在接受肾移植的hiv感染患者中，因为马拉韦洛克具有已知的抗逆转录病毒特性。这与意外的高拒绝率（高出2-3倍）特别相关

DESCRIPTION (provided by applicant): Despite considerable refinement in immunosuppressive regimens over the last 25 years and decreased rates of acute rejection following kidney transplantation, long-term transplant outcomes have not improved at the same rate and have remained stagnant. Furthermore, there has been a relative paucity in the development of new immunosuppressive strategies to minimize acute and chronic injury. Maraviroc is a CCR5 inhibitor that may have a novel role in modulating the immune response following transplantation. An ideal setting to test its impact on the alloimmune response is in HIV-infected patients undergoing kidney transplantation as maraviroc has known anti-retroviral qualities. This is particularly relevant in that unexpectedly high rejection rates (2-3 fold higher than HIV uninfected recipients) have been reported following kidney transplantation in HIV positive recipients. We hypothesize that CCR5 blockade will minimize immunologic graft injury and improve long-term kidney function. This hypothesis leads to the primary aim, which is to determine the impact of a CCR5 inhibitor (maraviroc) on improving long-term kidney graft function following kidney transplantation in HIV-infected recipients. Secondly, some evidence suggests that inhibition of CCR5 could reduce the size of the HIV viral reservoir during long-term antiretroviral therapy in people with HIV. We hypothesize that CCR5 blockade in combination with immunosuppressive therapy used following kidney transplantation will reduce HIV persistence in CD4+ T lymphocytes. Lastly, we hypothesize that the increased rejection reported in HIV+ patients may be due to increased frequency of heterologous memory donor-reactive T cells that arise as a result of chronic infections with HIV and a multitude of other co-pathogens such CMV, EBV, HCV, and HBV. Thus, transplantation in HIV+ patients may provide a unique opportunity to determine the importance of heterologous immunity to transplant outcomes in humans. This leads to the third aim, which is to assess the alloimmune status of HIV+ transplant patients and impact of CCR5 blockade on their alloimmune profile. To achieve these three aims, we propose a prospective, multi-center, double-blind phase II study of kidney transplantation in HIV+ individuals assessing the safety and efficacy of a maraviroc-based antiretroviral regimen given post-transplant. Subjects will be consented and enrolled until 120 eligible subjects are randomized. We will perform mechanistic analysis of the study subjects by testing collected blood samples at defined time points. The R34 grant will allow the investigators to finalize all facets of the clinical trial protocol, procedures for specimen collection, banking nd tracking, for confirming all participating centers, and preparing all necessary study documents and processes.