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

描述(由申请人提供)：尽管联合抗逆转录病毒疗法(CART)在减少HIV-1感染中与疾病相关的发病率和死亡率方面取得了压倒性的成功，但在强化治疗期间，病毒库仍然存在于潜伏感染的细胞中。治愈HIV-1的主要挑战是这些潜伏的病毒库的持久性，迫切需要在CART的背景下消除残留感染细胞的新策略。我们最近发现了一名患者，他在接受多个周期的抗体-药物结合物Brentuximab vedotin治疗难治性T细胞/间变性淋巴瘤后，细胞中缺乏可检测到的HIV-1。Brentuximab vedotin由一种与CD30结合的单抗组成，CD30是一种细胞表膜蛋白，在某些肿瘤细胞上表达，如与霍奇金淋巴瘤或其他类型的侵袭性淋巴瘤有关，但在静止的健康淋巴细胞上表达最低。布妥昔单抗与一种进入并选择性杀死抗体结合细胞的化合物结合。CD30在活化的淋巴细胞上表达，在更大程度上，在病毒感染后表达。HIV-1的复制和疾病的进展也与CD30的可溶性形式水平较高有关。此外，我们有初步数据表明，HIV-1感染或病毒重新激活的细胞可能优先表达CD30，使Brentuximab vedotin成为一种重要的、潜在的治疗剂，在HIV-1重新激活的情况下消除潜伏库。Brentuximab vedotin对HIV-1持久性的影响尚不清楚，值得进一步研究。我们假设，潜伏感染HIV-1的细胞可以通过转录病毒的重新激活而优先表达更高水平的CD30，而不是通过外源细胞因子或其他单独的T细胞刺激。因此，Brentixumab vedotin将选择性地靶向并清除病毒重新激活的细胞，从而缩小潜伏的HIV-1储存库的大小。我们对这笔赠款的R21部分的目的是：(1)在潜伏期的初级实验室模型中确定病毒重新激活与T细胞激活和CD30表达之间的关系，以及(2)确定HIV-1感染患者在抑制性抗逆转录病毒治疗中的细胞中的这些关系。我们针对R33组分的目的是：(3)确定Brentuximab vedotin治疗对潜伏的HIV-1储存库大小的影响，以及(4)在建立的人源化小鼠模型中对表面和可溶性CD30表达以及外周血和组织中T细胞激活的影响。拟议的创新研究将为如何使用抗体-药物结合物选择性地靶向和清除HIV-1感染细胞提供重要的见解，并有助于开发新的战略来对抗HIV-1的持久性。

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.