Advancing MHC-E-Restricted T cells as a Universal Immunotherapeutic

项目摘要 截至2018年底，联合国估计有3800万人感染艾滋病毒/艾滋病，其中170万人 新的感染。虽然预防性疫苗将大大阻止这种流行病， 在HIV-1感染者中，不仅可以遏制新的感染，还可以大大减少社会 维持如此多人的持续终身抗逆转录病毒治疗所需的负担。不幸的是，细胞治疗 体内清除HIV-1感染细胞的干预措施相对有限。MHC-E限制性CD 8 + T细胞可能 代表了一种普遍适用的治疗方法。只有两个几乎相同的HLA-E等位基因 在大多数人群中，MHC-E限制性HIV特异性T细胞受体可用作免疫调节剂。 供体非限制性治疗试剂。编码SIV抗原的菌株68-1 RhCMV载体（RhCMV/SIV）是 能够严格控制SIV复制，并且这种保护依赖于SIV特异性 MHC-E限制性CD 8 + T细胞。尽管它的预防效用，RhCMV诱导效应记忆CD 8 + T细胞 针对HIV/SIV进入门户的反应，而不是大部分SIV驻留的次级淋巴组织 在慢性感染期间。先前的研究已经证明，用CXCR 5转导的CD 8 + T细胞运输到T细胞， 淋巴结B细胞滤泡是SIV/HIV储库的关键部位。在这个提议中，我们将测序全长MHC- 来自RhCMV/SIV疫苗接种的猕猴的E限制性T细胞受体严格控制SIV复制。 我们将产生表达这些MHC-E-TCR和CXCR 5的自体CD 8 + T细胞转导子，并将其输注到 感染SIV的ART抑制恒河猴。ART发布后，我们将结合使用 组织染色和单细胞RNA测序，以评估这些转导子是否运输到B细胞卵泡 并对感染的病毒产生细胞作出反应而激活。此外，我们将评估MHC-E-TCR是否 转导子延迟病毒反弹。该项目中概述的实验可能构成一种新的 为HIV-1感染者提供替代性普遍治疗干预。

PROJECT SUMMARY At the end of 2018, the United Nations estimated that 38 million people were living with HIV/AIDS with 1.7 million new infections. Although a prophylactic vaccine would do much to halt this epidemic, attaining durable remission among HIV-1 infected individuals would not only curb new infections but also dramatically reduce the societal burden required to maintain continuous life-long ART treatment for so many. Unfortunately, cellular therapeutic interventions to purge HIV-1 infected cells in vivo are relatively limited. MHC-E-restricted CD8+ T cells may represent a universally applicable therapeutic approach. With only two nearly identical HLA-E alleles expressed in the majority of the human population, MHC-E-restricted HIV-specific T cell receptors could be utilized as a donor unrestricted therapeutic reagent. Strain 68-1 RhCMV vectors encoding SIV antigens (RhCMV/SIV) are capable of stringently controlling SIV replication, and that protection is dependent on the induction of SIV-specific MHC-E-restricted CD8+ T cells. Despite its prophylactic utility, RhCMV induces an effector memory CD8+ T cell response directed at portals of HIV/SIV entry not secondary lymphoid tissues where the bulk of SIV resides during chronic infection. Prior studies have demonstrated that CD8+ T cells transduced with CXCR5 traffic to the lymph node B-cell follicle a key site of the SIV/HIV reservoir. In this proposal, we will sequence full length MHC- E-restricted T cell receptors from RhCMV/SIV vaccinated macaques that stringently controlled SIV replication. We will generate autologous CD8+ T cell transductants expressing these MHC-E-TCR and CXCR5 and infuse them into SIV-infected ART-suppressed rhesus macaque. After release of ART, we will use a combination of tissue staining and single-cell RNA sequencing to assess whether these transductants traffic to the B-cell follicle and activate in response to infected virus-producing cells. In addition, we will assess whether MHC-E-TCR transductants delay viral rebound. The experiments outlined in this project may form the basis of a new alternative universal therapeutic intervention for those infected with HIV-1.