Elimination of HIV using HERV specific T cells

描述（由申请人提供）：除了少数例外，用于增强HIV-1感染者自然免疫力的免疫治疗策略在很大程度上令人失望。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得到了证明。法国的“维斯康蒂”患者接受了早期抗逆转录病毒药物治疗，然后停止服用药物。他们自身的免疫系统似乎在检测不到的情况下抑制了病毒的复制。在SIV感染的疫苗模型中，通过rhcmv载体方法产生强大的免疫力，导致动物在感染后无法检测到病毒载量。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，人们已经做出了重大努力，以确定哪些免疫原可能导致保守免疫。随着这一领域朝着从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。更强化的HAART治疗、将病毒“冲洗”出潜伏库的策略、增强免疫反应，都是实现功能性治愈的重要目标。在过去的两年里，随着第一批患者明显“治愈”了他们的艾滋病毒感染，人们越来越兴奋。在我们目前的拨款中，重新提交R01拨款的竞争性续期，我们已经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，在HIV-1感染的背景下，当细胞被重新激活时，它们代表着保守的、不可变的靶标（与HIV产生的高度多样化和快速变化的抗原相反）。我们最近发现，herv - k特异性CD8+ T细胞克隆可以消除感染多种HIV-1、HIV-2和SIV毒株的细胞。这表明，再激活的herv可能作为hiv -1感染细胞上的保守的宿主编码靶标，导致它们的细胞毒性裂解，并且它们可能被用于治疗性疫苗策略。这笔赠款提出了3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，我们将鉴定具有抗hiv的HERV特异性T细胞克隆

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.