Enhancing control of HIV by inhibiting TRAILshort

描述(申请人提供)：已有效治愈艾滋病毒的柏林患者为从人类宿主治愈艾滋病毒感染的可行性提供了概念证明。可能至少有四个因素导致柏林患者的艾滋病毒被治愈：(I)在骨髓移植前对艾滋病毒感染的长期和持久控制，(Ii)细胞毒性化疗杀死病毒库，(Iii)将抗感染的CCR5 Delta 32细胞移植到体内，以及(Iv)能够根除任何残余感染的广泛有效的免疫反应。这一案例引发了许多关于如何使艾滋病毒的治愈更具普遍性和可实现的结果的科学辩论和猜测。鉴于目前抗逆转录病毒药物的效力，目前的工作重点是开发杀死或清除病毒库的新方法(例如SAHA)，开发产生抵抗感染的细胞的新方法(例如CCR5的锌指核酸酶)，以及加强艾滋病毒的免疫控制。肿瘤坏死因子相关的凋亡诱导因子(TRAIL)是一种主要作用于免疫监视的分子，它与多种恶性肿瘤以及包括HIV在内的病毒感染的发病机制密切相关。关于TRAIL在HIV中的作用，相当多的证据支持在体内HIV感染过程中发生TRAIL失调的作用，并且有充分的证据表明，用外源性TRAIL治疗HIV感染患者的细胞，减少了潜伏感染细胞的数量，这是通过定量共培养分析中无法检测到的复制能力病毒水平来衡量的。由于TRAIL是由免疫系统的效应细胞(即CD8和/或NK细胞)表达的，我们质疑为什么依赖TRAIL的自然免疫机制不能独立地减少潜伏感染细胞的数量。我们发现来自HIV感染患者的细胞产生一种新的TRAIL剪接变体，我们称之为TRAILShort，它拮抗正常的TRAIL信号。因此，我们提出了一个模型，在这个模型中，HIV感染细胞产生TRAIL Short可以防止这些细胞被CTL或NK细胞杀死，这允许感染细胞的子集持续存在。目前的研究建议涉及了解这种TRAIL剪接变体的生物学原理并开发抑制方法，我们将其命名为TRAILShort(Trails)。由于我们已经产生的初步数据表明，TRAILS可以阻止HIV诱导的对CD4T细胞的杀伤，以及CTL和NK细胞诱导的杀伤，因此我们现在建议抑制TRAILS，作为一种提高HIV感染的CD4T细胞死亡率的手段，从而有助于根除HIV感染的细胞和治愈HIV感染。在这方面，我们有更多的初步数据表明，抑制TRAILS达到了增加对HIV感染的T细胞的杀伤，并增强对靶细胞的CTL和NK细胞杀伤的目标。

DESCRIPTION (provided by applicant): The Berlin patient who has been effectively cured from HIV provides proof of concept for the feasibility of curing HIV infection from the human host. It is likely that at least four factors have contributed to HIV being cured in the Berlin patient: (i) prolonged and durable control of HIV infection prior to bone marrow transplant, (ii) cytotoxic chemotherapy killing the viral reservoir, (iii) being transplanted with CCR5 delta 32 cells which are resistant to infection, and (iv) a broadly effective immune response which was able to eradicate any residual infection. This case has spurred much scientific debate and speculation as to how to make cure of HIV a more generalizable and an achievable outcome. Given the potency of current antiretroviral agents, current efforts are focusing on developing novel ways of killing or purging the viral reservoir (eg SAHA), developing new approaches to generate cells which resist infection (eg Zinc finger nucleases for CCR5) and enhancing the immune control of HIV. TNF related apoptosis inducing factor (TRAIL) is a molecule whose principal function is as an effector of immune surveillance, and it has been implicated in the pathogenesis of both malignancies, as well as viral infections including HIV. Concerning the role of TRAIL in HIV, considerable evidence supports a role for TRAIL dysregulation occurring during HIV infection in vivo, and there is ample evidence that treatment of cells from HIV-infected patients on HAART with exogenous TRAIL, reduces the number of latently infected cells, as measured by undetectable levels of replication competent virus in quantitative co-culture assays. Since TRAIL is expressed by effector cells (i.e., CD8 and/or NK cells) of the immune system, we questioned why TRAIL-dependent natural immune mechanisms do not independently reduce the number of latently infected cells. We found that cells from HIV-infected patients produce a novel splice variant of TRAIL which we call TRAILshort, which antagonizes normal TRAIL signaling. We therefore propose a model whereby the production of TRAILshort by HIV-infected cells prevents these cells from being killed by either CTL or NK cells, and this allows a subset of infected cells to persist. The current research proposal concerns gaining understanding the biology of and developing ways to inhibit this TRAIL splice variant, which we have named TRAILshort (TRAILs). Since we have generated preliminary data which demonstrates that TRAILs blocks HIV induced killing of CD4 T cells, as well as killing induced by CTL and NK cells, we now propose to inhibit TRAILs as a means of increasing the rate at which HIV infected CD4 Tcells die, and thereby contributing to the goal of eradicating HIV infected cells, and a cure for HIV infection. In this regard, we have additional preliminary data indicating that inhibiting TRAILs achieves the goal of increasing killing of HIV infected T-cells, and enhancing both CTL and NK cell killing of target cells.