Elimination of HIV using HERV specific T cells

描述（由申请人提供）：免疫策略，以提高对HIV-1感染者的自然免疫力，在很大程度上是令人失望的，只有少数例外。然而，最近，自然免疫反应的力量已经在人类和非人类灵长类动物模型中显示出来。法国的“维斯康蒂”患者早期接受了抗逆转录病毒药物治疗，随后停止服药。它们自身的免疫系统似乎能抑制病毒复制，使其检测不到。在SIV感染的疫苗模型中，通过rhCMV-载体方法产生的强大免疫力导致动物在感染后具有不可检测的病毒载量。然而，病毒变异和免疫逃逸仍然是疫苗诱导或天然免疫的主要障碍，并且已经做出了重大努力来确定哪些免疫原可能导致保守免疫。随着这一领域朝着从受感染者身上消除艾滋病毒的梦想迈进，似乎需要采取综合办法。更密集的HAART治疗，将病毒从潜伏库中“冲洗”出来的策略，增强免疫反应对于功能性治愈的目标都很重要。在过去的两年里，随着第一批艾滋病毒感染者明显“治愈”，人们越来越兴奋。在我们目前的补助金中，重新提交了R 01补助金的竞争性更新，我们开发了一种新的范例。人类内源性逆转录病毒（HERV）HERV固定在我们的DNA中，并且代表在HIV-1感染的情况下重新激活时细胞裂解的保守的、不可变的靶标（与HIV产生的高度多样性和快速变化的抗原相反）。我们最近发现HERV-K特异性CD 8 + T细胞克隆可以消除感染不同HIV-1，HIV-2和SIV毒株的细胞。这表明，重新激活的HERV可能作为HIV-1感染细胞上的保守的宿主编码靶标，导致其细胞毒性裂解，并且它们可能在治疗性疫苗策略中被利用。该基金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。在第二个具体目标中，我们将鉴定具有抗HIV的HERV特异性T细胞克隆。 体外活性在第三个具体目标中，我们将测试HERV特异性T细胞在人源化小鼠模型中控制或消除HIV-1感染的能力。我们先前的资助产生的数据表明，HIV-1感染导致HERV表达并刺激HERV特异性免疫应答，这可以在体外消除HIV-1感染。该更新申请建立在先前的授权基础上，以解决HIV-1感染后表达的HERV，从而确定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。这项资助中提出的工作直接通往未来HERV特异性T细胞消除HIV-1感染的人体试验。

DESCRIPTION (provided by applicant): 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. n 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 ontrol 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.