Elimination of HIV using HERV specific T cells

使用 HERV 特异性 T 细胞消除 HIV

• 批准号: 8731533
• 负责人: DOUGLAS F NIXON
• 金额: $ 48.45万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-05 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8731533
• 关键词: Address; Adoptive Transfer; Animal Model; Animals; Anti-Retroviral Agents; Antigens; Autoantigens; Berlin; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Count; Cells; Characteristics; Chronic; Cytolysis; DNA; Data; Detection; Disease; Dreams; Endogenous Retroviruses; Evolution; Family; Flushing; Fossils; France; Frequencies; Future; Generations; Genetic Transcription; Genome; Goals; Grant; HERVs; HIV; HIV Infections; HIV-1; HIV-2; Highly Active Antiretroviral Therapy; Human; Immune; Immune response; Immune system; Immunity; Immunotherapeutic agent; In Vitro; Infection; Intervention; Lead; Leukocytes; Modeling; Monkeys; Mus; Natural Immunity; Patients; Persons; Pharmaceutical Preparations; Pharmacotherapy; Proviruses; Publishing; Reading Frames; Retroviridae; Route; SIV; T cell response; T-Lymphocyte; Testing; Therapeutic; Vaccines; Variant; Viral; Viral Load result; Virus; Work; cytotoxic; in vitro activity; in vivo; innovation; killings; mouse model; nonhuman primate; novel; protective effect; public health relevance; purge; therapeutic vaccine; vector

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.

描述(由申请人提供)：提高感染者对HIV-1的自然免疫力的免疫治疗策略在很大程度上令人失望，除了少数例外。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”患者接受了早期抗逆转录病毒药物治疗，随后停止服药。他们自己的免疫系统似乎在检测到的情况下抑制了病毒复制。在SIV感染的疫苗模型中，通过重组巨细胞病毒载体方法产生强大的免疫力，导致感染后病毒载量无法检测到的动物。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，将病毒从潜伏的储存库中“冲洗”出来的策略，增强免疫反应，这些都是实现功能性治愈目标的重要因素。在过去的两年里，随着第一批患者显然已经治愈了他们的艾滋病毒感染，人们的兴奋情绪已经建立起来。在我们目前的赠款中，我们开发了一种新的范式，这是对R01赠款的竞争性续签的重新提交。人类内源性逆转录病毒(HERV)HERV固定在我们的DNA中，当在HIV-1感染的背景下重新激活时，HERV代表保守的、不变的靶标(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细胞克隆可以清除感染不同HIV-1、HIV-2和SIV毒株的细胞。这表明，重新激活的HERV可能在HIV-1感染细胞上作为保守的、宿主编码的靶点，导致它们的细胞毒裂解，并且它们可能被开发成治疗性疫苗策略。这项拨款提出了三个具体目标。在第一个特定目标中，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，我们将鉴定抗HIV的HERV特异性T细胞克隆 体外活性。在第三个特定目标中，我们将在人源化小鼠模型中测试HERV特异性T细胞控制或消除HIV-1感染的能力。我们之前的资助提供的数据表明，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。这一续签申请建立在先前拨款的基础上，以解决哪些HERV在HIV-1感染后表达，从而哪些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上测试功能。这项拨款中提议的工作为未来进行HERV特异性T细胞的人体试验以消除HIV-1感染提供了一条直接途径。