Targeting latent HIV-1 Reservoirs with the Antibody-Drug Conjugate, Brentuximab Vedotin

描述（由申请方提供）：尽管联合抗逆转录病毒治疗（cART）在降低HIV-1感染的疾病相关发病率和死亡率方面取得了压倒性成功，但在强化治疗期间，病毒储库在潜伏感染细胞中持续存在。实现HIV-1治愈的主要挑战是这些潜伏病毒库的持续存在，迫切需要在cART环境中消除残留感染细胞的新策略。我们最近发现了一例接受多个周期的抗体-药物偶联物维布妥昔单抗治疗难治性T细胞/复发性淋巴瘤后，细胞中缺乏可检测到的HIV-1的个体。维布妥昔单抗由一种与CD 30结合的单克隆抗体组成，CD 30是一种细胞表面膜蛋白，在某些肿瘤细胞上表达，如霍奇金淋巴瘤或其他类型的侵袭性淋巴瘤，但在静息健康淋巴细胞上表达最低。维布妥昔单抗与一种化合物结合，该化合物可进入并选择性杀死抗体结合细胞。CD 30在活化的淋巴细胞上表达，并且在病毒感染后更大程度上表达。HIV-1复制和疾病进展也与更高水平的可溶性形式的CD 30相关。此外，我们的初步数据表明，HIV-1感染或病毒再活化的细胞可能优先表达CD 30，使维布妥昔单抗成为消除HIV-1再活化背景下潜伏储库的重要潜在治疗药物。目前尚不清楚维布妥昔单抗对HIV-1持续性的影响，需要进一步研究。我们假设，潜伏HIV-1感染的细胞可以诱导优先表达更高水平的CD 30的转录病毒再激活比T细胞刺激外源性细胞因子或其他药物单独。因此，Brentixumab vedotin将选择性靶向并清除病毒再活化细胞，从而缩小潜伏HIV-1储库。本基金R21部分的目的是：（1）在潜伏期的主要实验室模型中确定病毒再活化与T细胞活化和人CD 4 + T淋巴细胞上CD 30表达之间的关系，以及（2）在接受抑制性抗逆转录病毒治疗的HIV- 1感染患者的细胞中确定这些关系。R33组分的目的是：（3）确定维布妥昔单抗治疗对潜伏HIV-1储库大小的影响，以及（4）在已建立的人源化小鼠模型中对外周血和组织中表面和可溶性CD 30表达以及T细胞活化的影响。拟议的创新研究将为抗体-药物偶联物如何用于选择性靶向和清除HIV-1感染细胞提供重要见解，并有助于开发对抗HIV-1持久性的新策略。

DESCRIPTION (provided by applicant): Despite the overwhelming success of the ability of combination antiretroviral therapy (cART) to reduce disease-related morbidity and mortality in HIV-1 infection, viral reservoirs persist in latently infected cells during intensive therapy. The main challenge in achieving a cure for HIV-1 is the persistence of these latent viral reservoirs, and novel strategies to eliminate residual infected cells in the setting of cART are urgently needed. We have recently identified an individual who lacked detectable HIV-1 in cells after receiving multiple cycles of the antibody-drug conjugate, brentuximab vedotin for refractory T cell/anablastic lymphoma. Brentuximab vedotin consists of a monoclonal antibody that binds to CD30, a cell surface membrane protein, that is expressed on certain tumor cells, such as those involved with Hodgkin's or other types of aggressive lymphomas, but minimally expressed on resting, healthy lymphocytes. Brentuximab is conjugated with a compound which enters and selectively kills antibody-bound cells. CD30 is expressed on activated lymphocytes, and to a greater extent, after viral infection. HIV-1 replication and disease progression have also been associated with higher levels of the soluble form of CD30. Furthermore, we have preliminary data that suggest that HIV-1-infected or viral reactivated cells may preferentially express CD30, making brentuximab vedotin an important, potential therapeutic agent for eliminating latent reservoirs in the setting of HIV-1 reactivation. The impact of brentuximab vedotin on HIV-1 persistence is not known and warrants further study. We hypothesize that latently HIV-1-infected cells can be induced to preferentially express higher levels of CD30 by transcriptional viral reactivation than by T-cell stimulation from exogenous cytokines or other agents alone. Brentixumab vedotin will therefore selectively target and clear viral reactivated cells leading to smaller latent HIV-1 reservoir size. Our aims for the R21 component of this grant are to: (1) determine the relationships between viral reactivation and T-cell activation and CD30 expression on human CD4+ T lymphocytes in primary laboratory models of latency, and, (2) determine these relationships in cells from HIV- 1-infected patients on suppressive antiretroviral therapy. Our aims for the R33 component are to: (3) determine the effects of brentuximab vedotin treatment on latent HIV-1 reservoir size, and, (4) on surface and soluble CD30 expression and T-cell activation in peripheral blood and tissue in an established humanized mouse model. The proposed, innovative studies will provide important insights into how antibody-drug conjugates can be used to selectively target and clear HIV-1-infected cells and aid in the development of novel strategies to combat HIV-1 persistence.