Elimination of Latently HIV-infected Cells from Antiretroviral Therapy-suppressed Subjects by Engineered Immune-mobilizing T-cell Receptors.
Elimination of Latently HIV-infected Cells from Antiretroviral Therapy-suppressed Subjects by Engineered Immune-mobilizing T-cell Receptors.
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通过工程化的免疫动力T细胞受体从抗逆转录病毒治疗受试者中消除了潜在的HIV感染细胞。
DOI：
10.1038/mt.2016.114
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发表时间：
2016-11
期刊：
影响因子：
--
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中科院分区：
文献类型：
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人类免疫缺陷病毒（HIV）在长期存活的CD 4 + T细胞中持续处于潜伏状态是根除的主要障碍。潜伏期逆转剂，诱导直接或免疫介导的细胞死亡后重新激活的艾滋病毒是一个可能的解决方案。然而，清除重新激活的细胞可能需要经过微调的免疫治疗剂，以检测低水平表达的病毒抗原。我们测试了针对病毒的免疫动员单克隆T细胞受体（ImmTAV）的抗病毒功效，ImmTAV是重定向CD 8 + T细胞以杀死HIV感染的CD 4 + T细胞的双特异性分子。对免疫显性Gag表位SL 9及其逃逸变体具有特异性的T细胞受体进行工程化以实现超生理亲和力，并与人源化CD 3特异性单链抗体片段融合。通过免疫动员抗病毒的单克隆T细胞受体，体外多克隆CD 8 + T细胞被有效地重定向，以在体外诱导型HIV再活化后消除人类组织相容性白细胞抗原（HLA）-A*0201阳性抗逆转录病毒治疗患者的CD 4 + T细胞。感染细胞清除效率与HIV Gag表达相关。抗病毒的免疫动员单克隆T细胞受体有可能作为一种治疗方法，以促进重新激活的HIV储库细胞的清除。
Persistence of human immunodeficiency virus (HIV) in a latent state in long-lived CD4+ T-cells is a major barrier to eradication. Latency-reversing agents that induce direct or immune-mediated cell death upon reactivation of HIV are a possible solution. However, clearance of reactivated cells may require immunotherapeutic agents that are fine-tuned to detect viral antigens when expressed at low levels. We tested the antiviral efficacy of immune-mobilizing monoclonal T-cell receptors against viruses (ImmTAVs), bispecific molecules that redirect CD8+ T-cells to kill HIV-infected CD4+ T-cells. T-cell receptors specific for an immunodominant Gag epitope, SL9, and its escape variants were engineered to achieve supraphysiological affinity and fused to a humanised CD3-specific single chain antibody fragment. Ex vivo polyclonal CD8+ T-cells were efficiently redirected by immune-mobilising monoclonal T-cell receptors against viruses to eliminate CD4+ T-cells from human histocompatibility leukocyte antigen (HLA)-A*0201-positive antiretroviral therapy-treated patients after reactivation of inducible HIV in vitro. The efficiency of infected cell elimination correlated with HIV Gag expression. Immune-mobilising monoclonal T-cell receptors against viruses have potential as a therapy to facilitate clearance of reactivated HIV reservoir cells.
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DOI：
10.4049/jimmunol.1103138
发表时间：
2012-04-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Hong JJ;Amancha PK;Rogers K;Ansari AA;Villinger F
通讯作者：
Villinger F
影响因子：
12.4
作者：
Lam, Sharon;Sung, Julia;Bollard, Catherine
通讯作者：
Bollard, Catherine
影响因子：
6.7
作者：
Kitchen SG;Levin BR;Bristol G;Rezek V;Kim S;Aguilera-Sandoval C;Balamurugan A;Yang OO;Zack JA
通讯作者：
Zack JA
影响因子：
20.3
作者：
Leen, Ann M.;Bollard, Catherine M.;Heslop, Helen E.
通讯作者：
Heslop, Helen E.
影响因子：
64.8
作者：
Deng, Kai;Pertea, Mihaela;Rongvaux, Anthony;Wang, Leyao;Durand, Christine M.;Ghiaur, Gabriel;Lai, Jun;McHugh, Holly L.;Hao, Haiping;Zhang, Hao;Margolick, Joseph B.;Gurer, Cagan;Murphy, Andrew J.;Valenzuela, David M.;Yancopoulos, George D.;Deeks, Steven G.;Strowig, Till;Kumar, Priti;Siliciano, Janet D.;Salzberg, Steven L.;Flavell, Richard A.;Shan, Liang;Siliciano, Robert F.
通讯作者：
Siliciano, Robert F.