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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：
9744988
负责人：
DOUGLAS F NIXON
金额：
$ 59.32万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-23 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9744988
关键词：
Elimination HIV using HERV specific

项目摘要

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.

项目摘要增强感染者对 HIV-1 自然免疫力的免疫治疗策略在很大程度上已经取得了进展。令人失望的是，除了少数例外。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得到证实。法国“维斯康蒂”患者早期接受治疗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会抑制病毒复制低于检测水平。在 SIV 感染的疫苗模型中，通过 rhCMV 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，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。随着领域向梦想迈进为了消除感染者体内的艾滋病毒，似乎需要采取综合方法。更密集 HAART 疗法、将病毒“冲出”潜伏病毒库的策略、增强免疫反应都是如此对于功能性治愈的目标很重要。在过去的两年里，第一批患者的到来让人们兴奋不已显然他们的艾滋病毒感染已经“治愈”。在我们目前的资助中，重新提交有竞争力的更新 R01 资助后，我们开发了一种新颖的范例。人内源性逆转录病毒（HERV） HERV 固定在我们的 DNA 中，代表保守的、不可变的靶标（与高度多样化和 HIV 产生的快速变化的抗原）在 HIV-1 感染的情况下重新激活时可用于细胞裂解。我们最近证明 HERV-K 特异性 CD8+ T 细胞克隆可以消除感染多种 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目标作用于 HIV-1 感染的细胞，导致其细胞毒性裂解，并且它们有可能被用于治疗疫苗策略。这笔赠款提出了 3 个具体目标。在第一个具体目标中，我们将确定哪种 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 HERV 特异性 T 细胞克隆具有体外抗HIV活性。在第三个具体目标中，我们将测试 HERV 特异性 T 细胞的控制能力或消除人源化小鼠模型中的 HIV-1 感染。我们之前的资助产生的数据表明 HIV-1 感染导致 HERV 表达并刺激 HERV 特异性免疫反应，这可能体外消除 HIV-1 感染。此次续签申请以之前的拨款为基础，旨在解决哪些 HERV 问题 HIV-1 感染后表达，因此 HERV 特异性 T 细胞最有可能发挥功能。我们将测试 HIV-1 感染人源化小鼠模型的功能。这笔赠款中提议的工作有未来通过 HERV 特异性 T 细胞进行人体试验以消除 HIV-1 感染的直接途径。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

T cell responses to human endogenous retroviruses in HIV-1 infection.

DOI：
10.1371/journal.ppat.0030165
发表时间：
2007-11
期刊：
PLoS pathogens
影响因子：
6.7
作者：
Garrison KE;Jones RB;Meiklejohn DA;Anwar N;Ndhlovu LC;Chapman JM;Erickson AL;Agrawal A;Spotts G;Hecht FM;Rakoff-Nahoum S;Lenz J;Ostrowski MA;Nixon DF
通讯作者：
Nixon DF

Specific human endogenous retroviruses predict metastatic potential in uveal melanoma.

DOI：
10.1172/jci.insight.147172
发表时间：
2022-05-09
期刊：
JCI INSIGHT
影响因子：
8
作者：
Bendall, Matthew L.;Francis, Jasmine H.;Shoushtari, Alexander N.;Nixon, Douglas F.
通讯作者：
Nixon, Douglas F.

Human Endogenous Retrovirus Expression Is Upregulated in the Breast Cancer Microenvironment of HIV Infected Women: A Pilot Study.

DOI：
10.3389/fonc.2020.553983
发表时间：
2020
期刊：
Frontiers in oncology
影响因子：
4.7
作者：
Curty G;Beckerle GA;Iñiguez LP;Furler RL;de Carvalho PS;Marston JL;Champiat S;Heymann JJ;Ormsby CE;Reyes-Terán G;Soares MA;Nixon DF;Bendall ML;Leal FE;de Mulder Rougvie M
通讯作者：
de Mulder Rougvie M

The Psychiatric Risk Gene NT5C2 Regulates Adenosine Monophosphate-Activated Protein Kinase Signaling and Protein Translation in Human Neural Progenitor Cells