Elimination of HIV using HERV specific T cells

使用 HERV 特异性 T 细胞消除 HIV

基本信息

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
项目类别：
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

项目摘要

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）：免疫治疗策略，以增强感染者对HIV-1的自然免疫力，这在很大程度上令人失望，但有少数例外。然而，最近，自然免疫反应的力量已在人类和非人类灵长类动物模型中显示出来。法国的“ Visconti”患者接受了早期的抗逆转录病毒药物治疗，然后停止服用药物。他们自己的免疫系统似乎抑制了在检测下的病毒复制。在SIV感染的疫苗模型中，通过RHCMV-vector方法产生强大的免疫力导致感染后具有无法检测到的病毒载量的动物。但是，病毒变异和免疫逃生仍然是疫苗诱导或自然免疫的主要障碍，并且已经为确定哪些免疫原子可能导致保守的免疫力做出了重大努力。随着该领域朝着从受感染者中消除艾滋病毒的梦想时，似乎需要采取组合方法。更密集的HAART疗法，从潜在储层中“冲洗”病毒的策略，在功能治疗的目标中，增强免疫反应都是重要的。在过去的两年中，兴奋与最初的患者显然“治愈”了其HIV感染。 n我们目前的赠款是R01赠款的竞争性更新的重新提交，我们开发了一种新颖的范式。人体内源性逆转录病毒（HERV）HERV固定在我们的DNA中，代表了保守的，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比），当在HIV-1感染中重新激活时，用于细胞裂解。我们最近表明，HERV-K特异性CD8+ T细胞克隆可以消除感染不同HIV-1，HIV-2和SIV菌株的细胞。这表明重新激活的HERV可以用作HIV-1感染细胞的保守，宿主编码的靶标，从而导致其细胞毒性裂解，并有可能在治疗性疫苗策略中被利用。该赠款提出了3个具体目标。在第一个特定目的中，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，我们将识别具有抗HIV的HERV特定T细胞克隆体外活性。在第三个特定目的中，我们将测试HERV特异性T细胞在人源化小鼠模型中侵袭或消除HIV-1感染的能力。我们以前的赠款产生了数据，该数据表明HIV-1感染会导致HERV表达并刺激HERV特异性免疫反应，从而可以在体外消除HIV-1感染。该更新应用基于先前的赠款，以解决HERV在HIV-1感染后表达的，因此特定于HERV特定的T细胞最有可能起作用。我们将在HIV-1感染的人源化小鼠模型中测试功能。该赠款中提出的工作有直接通往HERV特定T细胞的未来人类试验，以消除HIV-1感染。