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.

项目摘要在受感染者中，可以提高对HIV-1的自然免疫力的免疫治疗策略很大程度上令人失望，有少数例外。然而，最近，自然免疫反应的力量具有它们以人类和非人类灵长类动物模型显示。法国的“ Visconti”患者提早接受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病毒复制以下检测。在SIV感染的疫苗模型中，通过A产生强大的免疫力 RHCMV-VECTOR方法导致感染后具有无法检测到的病毒载量的动物。但是，病毒变化和免疫逃生仍然是疫苗诱导或自然免疫的主要障碍，并且已经进行了重大努力确定哪些免疫原可能导致免疫学构成免疫学。随着田野向梦的发展从感染者中消除艾滋病毒，似乎需要采用组合方法。更密集 HAART治疗，从潜在储层中“冲洗”病毒的策略，促进免疫复杂的策略都是在功能治疗的目标中很重要。在过去的两年中，兴奋与第一批患者建立了显然“治愈”了他们的艾滋病毒感染。在我们目前的赠款中，重新提出竞争性续签R01赠款，我们已经开发了一种新颖的范式。人内源性逆转录病毒（HERVS） HERV固定在我们的DNA中，代表构成不变的目标（与高度多样化和当HIV-1感染中重新激活HIV时，HIV产生的抗原快速变化。我们最近表明，HERV-K特异性CD8+ T细胞克隆可以消除感染Diver HIV-1的细胞， HIV-2和SIV菌株。这表明重新激活的HERV可以用作配置，主机编码的目标在HIV-1感染的细胞上，导致其细胞毒性裂解，并有可能在治疗中利用它们疫苗策略。这项赠款提案3特定目标。在第一个特定目标中，我们将确定哪个HERV 序列在HIV-1感染中表达。在第二个特定目标中，我们将确定HERV特定的T细胞克隆体外具有抗HIV活性。在第三个特定目的中，我们将测试特定的T细胞的控制能力或消除人性化小鼠模型中的HIV-1感染。我们以前的赠款产生的数据表明 HIV-1感染会导致HERV表达并刺激HERV特异性免疫响应，这可能消除体外HIV-1感染。此更新申请基于上一笔的赠款，以解决HERVS 在HIV-1感染后表达，因此特定的T细胞最有可能发挥作用。我们将在HIV-1感染的人源化小鼠模型中测试功能。这笔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。

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）

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

DOI：
10.1016/j.biopsych.2019.03.977
发表时间：
2019-07-15
期刊：
BIOLOGICAL PSYCHIATRY
影响因子：
10.6
作者：
Duarte, Rodrigo R. R.;Bechtel, Nathaniel D.;Srivastava, Deepak P.
通讯作者：
Srivastava, Deepak P.

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