T cell responses to human endogenous retroviruses in HIV-1 infection.
T cell responses to human endogenous retroviruses in HIV-1 infection.
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DOI：
10.1371/journal.ppat.0030165
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发表时间：
2007-11
期刊：
影响因子：
6.7
通讯作者：
Nixon DF
中科院分区：
文献类型：
--
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
人类内源性逆转录病毒（HERV）是已整合到人类基因组中的古老感染因子的残留物。在正常情况下，HERV是功能缺陷的或受宿主因素控制。在HIV-1感染的个体中，细胞内防御机制受到损害。我们假设HIV-1感染会消除或改变对HERV活性的控制。HERV的表达可以潜在地刺激T细胞对HERV抗原的应答，并且在HIV-1/HERV相似的区域中，这些T细胞可以是交叉反应性的。我们确定HIV-1阳性个体的HERV产生水平超过HIV-1阴性对照。为了研究HERV活性对特异性免疫的影响，我们检测了29名HIV-1阳性和13名HIV-1阴性研究参与者对HERV肽的T细胞应答。我们报告了HIV-1阳性研究参与者中通过ELISPOT分析检测到的HERV区域衍生肽的T细胞应答。我们发现抗HERV T细胞应答和HIV-1血浆病毒载量之间呈负相关。在HIV-1阳性个体中，我们证明了HERV特异性T细胞能够杀死呈递其同源肽的细胞。这些数据表明，HIV-1感染导致HERV表达和刺激HERV特异性CD 8 + T细胞应答。HERV特异性CD 8 + T细胞具有与在对HIV-1感染的应答中的重要作用一致的特征：与对有效控制的病毒（巨细胞病毒）应答的T细胞的表型相似，与HIV-1血浆病毒载量负相关，以及裂解呈递其靶肽的细胞的能力。这些特征表明，诱导抗HERV特异性免疫应答是一种新的免疫接种方法。由于内源性逆转录病毒序列固定在人类基因组中，它们提供了一个稳定的靶标，HERV特异性T细胞可以识别任何HIV-1病毒变体感染的细胞。HERV特异性免疫是研究HIV-1发病机制和疫苗设计的重要新途径。人类基因组包含许多古代病毒感染的残留物或化石，称为人类内源性逆转录病毒（HERV）。像化石一样，这些HERV在大多数情况下被认为是死亡或惰性的。然而，我们证明，当一个人感染了人类免疫缺陷病毒（HIV）时，人体免疫系统中的T细胞会对HERV产生反应。对HERV应答的T细胞与有效控制巨细胞病毒（一种常见的慢性病毒感染）的T细胞具有共同的特征。对HERV应答的T细胞也可以杀死携带HERV蛋白的靶细胞。对于一些HIV阳性的人来说，他们对HERV的反应强度与较低的HIV病毒载量有关。这项研究对HIV疫苗研究的新方向具有重要意义。制造有效的艾滋病毒疫苗的关键障碍之一是克服艾滋病毒复制时产生的一些病毒变异体逃避人体为控制感染而产生的免疫反应的能力。如果识别HERV的T细胞可以稳定地靶向HIV感染的细胞，它们可能是控制HIV感染的重要因素。
Human endogenous retroviruses (HERVs) are remnants of ancient infectious agents that have integrated into the human genome. Under normal circumstances, HERVs are functionally defective or controlled by host factors. In HIV-1-infected individuals, intracellular defense mechanisms are compromised. We hypothesized that HIV-1 infection would remove or alter controls on HERV activity. Expression of HERV could potentially stimulate a T cell response to HERV antigens, and in regions of HIV-1/HERV similarity, these T cells could be cross-reactive. We determined that the levels of HERV production in HIV-1-positive individuals exceed those of HIV-1-negative controls. To investigate the impact of HERV activity on specific immunity, we examined T cell responses to HERV peptides in 29 HIV-1-positive and 13 HIV-1-negative study participants. We report T cell responses to peptides derived from regions of HERV detected by ELISPOT analysis in the HIV-1-positive study participants. We show an inverse correlation between anti-HERV T cell responses and HIV-1 plasma viral load. In HIV-1-positive individuals, we demonstrate that HERV-specific T cells are capable of killing cells presenting their cognate peptide. These data indicate that HIV-1 infection leads to HERV expression and stimulation of a HERV-specific CD8+ T cell response. HERV-specific CD8+ T cells have characteristics consistent with an important role in the response to HIV-1 infection: a phenotype similar to that of T cells responding to an effectively controlled virus (cytomegalovirus), an inverse correlation with HIV-1 plasma viral load, and the ability to lyse cells presenting their target peptide. These characteristics suggest that elicitation of anti-HERV-specific immune responses is a novel approach to immunotherapeutic vaccination. As endogenous retroviral sequences are fixed in the human genome, they provide a stable target, and HERV-specific T cells could recognize a cell infected by any HIV-1 viral variant. HERV-specific immunity is an important new avenue for investigation in HIV-1 pathogenesis and vaccine design. The human genome contains a number of remnants or fossils of ancient viral infections referred to as human endogenous retroviruses (HERV). Like fossils, these HERV are considered to be dead or inert in most cases. However, we demonstrate that T cells in the human immune system respond to HERV when a person is infected with the human immunodeficiency virus (HIV). The T cells responding to HERV share characteristics with T cells that effectively control cytomegalovirus, a common chronic viral infection. T cells responding to HERV can also kill target cells carrying HERV protein. For some HIV-positive people, the strength of their response against HERV is related to having a lower HIV viral load. This study has important implications for new directions in HIV vaccine research. One of the key obstacles to creating an effective HIV vaccine is overcoming the ability of some of the viral variants produced when HIV replicates to evade the immune responses that the body mounts to control infections. If T cells that recognize HERV can stably target HIV-infected cells, they could be an important factor in controlling HIV infection.
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影响因子：
6.7
作者：
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通讯作者：
Bieniasz PD
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64.8
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作者：
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