Elimination of HIV using HERV specific T cells

项目摘要 免疫治疗策略在很大程度上提高了感染者对HIV-1的自然免疫力 令人失望，只有几个例外。然而，最近，自然免疫反应的力量已经 已在人类和非人类灵长类动物模型中显示。法国的“维斯康蒂”患者很早就接受了 接受抗逆转录病毒药物治疗，然后停止服用他们的药物。他们自己的免疫系统似乎抑制了 病毒复制低于检测范围。在SIV感染的疫苗模型中，通过一种 重组人巨细胞病毒载体方法导致动物感染后病毒载量检测不到。然而，病毒变异和 免疫逃逸仍然是疫苗诱导或自然免疫的主要障碍，主要努力是 以确定哪些免疫原可能导致保守免疫。当田野走向梦想的时候 要从感染者身上消除艾滋病毒，似乎需要采取综合办法。更密集 HAART疗法、将病毒从潜伏的储存库中“冲洗”出来的策略、增强免疫反应等都是 在功能性治疗的目标中很重要。在过去的两年里，第一批患者的兴奋情绪与日俱增 显然，他们的艾滋病毒感染已被“治愈”。在我们目前的拨款中，重新提交了一份竞争性的 为了续签R01赠款，我们开发了一种新的范式。人内源性逆转录病毒(HERV) HERV固定在我们的DNA中，代表保守的、不变的靶标(与高度多样化和 在HIV-1感染背景下重新激活时，用于细胞裂解的快速变化的抗原)。 我们最近发现，Herv-K特异性CD8+T细胞克隆可以消除感染不同HIV-1的细胞， HIV-2和SIV毒株。这表明重新激活的HERV可能作为保守的、宿主编码的靶标 在HIV-1感染的细胞上，导致它们的细胞毒性裂解，并且它们可能被利用在治疗 疫苗战略。这项拨款提出了三个具体目标。在第一个具体目标中，我们将确定哪些Herv 序列在HIV-1感染中表达。在第二个特定目标中，我们将鉴定HERV特异性T细胞克隆 在体外具有抗HIV活性。在第三个特定目标中，我们将测试HERV特异性T细胞的控制能力 或者在人源化的小鼠模型中消除HIV-1感染。我们之前的拨款产生的数据表明 HIV-1感染导致HERV表达，并刺激HERV特异性免疫反应，这可能 在体外消除HIV-1感染。此续订申请建立在上一次授权的基础上，以解决哪些HERV 在HIV-1感染后表达，因此哪些Herv特异性T细胞最有可能发挥功能。我们 将在HIV-1感染的人源化小鼠模型中测试功能。这项拨款中提议的工作有一个 直接进入未来的HERV特异性T细胞人体试验，以消除HIV-1感染。

PROJECT ABSTRACT Immunotherapeutic strategies to boost natural immunity against HIV-1 in those who are infected have largely been disappointing, with a few exceptions. Recently, however, the power of the natural immune response has been shown in human and nonhuman primate models. The “Visconti” patients in France received early antiretroviral drug therapy and then stopped taking their drugs. Their own immune systems appeared to suppress viral replication below detection. In a vaccine model of SIV infection, generation of powerful immunity through a rhCMV-vector approach led to animals with undetectable viral loads after infection. However, viral variation and immune escape is still a major impediment to vaccine induced or natural immunity, and major efforts have been made to determine which immunogens might lead to conserved immunity. As the field moves towards the dream of elimination of HIV from infected persons, combination approaches appear to be needed. More intensive HAART therapy, strategies to “flush” virus out of the latent reservoir, boosting of immune responses are all important in the goal of a functional cure. Over the past two years, excitement has built with the first patients apparently “cured” of their HIV infection. In our current grant, a resubmission of a competitive renewal of an R01 grant, we have developed a novel paradigm. Human endogenous retroviruses (HERVs) HERVs are fixed in our DNA, and represent conserved, immutable targets (in contrast to the highly diverse and rapidly changing antigens produced by HIV) for cellular lysis when reactivated in the context of HIV-1 infection. We recently showed that HERV-K-specific CD8+ T cell clones can eliminate cells infected with diverse HIV-1, HIV-2 and SIV strains. This indicates that reactivated HERVs may serve as conserved, host-encoded targets on HIV-1-infected cells, leading to their cytotoxic lysis, and that they can potentially be exploited in a therapeutic vaccine strategy. This grant proposes 3 specific aims. In the 1st specific aim we will identify which HERV sequences are expressed in HIV-1 infection. In the 2nd specific aim we will identify HERV specific T cell clones with anti-HIV activity in vitro. In the 3rd specific aim we will test HERV specific T cells for their ability to control or eliminate HIV-1 infection in the humanized mouse model. Our previous grant produced data that showed that HIV-1 infection leads to HERV expression and stimulates a HERV-specific immune response, which could eliminate HIV-1 infection in vitro. This renewal application builds on the previous grant to address which HERVs are expressed after HIV-1 infection, and thus which HERV specific T cells are most likely to be functional. We will test functionality in a humanized mouse model of HIV-1 infection. The work proposed in this grant has a direct route to a future human trial of HERV specific T cells to eliminate HIV-1 infection.