Targeting Non Viral Markers of HIV Persistence

针对 HIV 持续存在的非病毒标志物

基本信息

批准号：
9906848
负责人：
Timothy Jensen Henrich
金额：
$ 70.35万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-15 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9906848
关键词：
Antibody-drug conjugates Aspirate substance Binding Bispecific Antibodies Bispecific Monoclonal Antibodies Blood Bronchoalveolar Lavage CD4 Positive T Lymphocytes Cell surface Cells Clinical Clinical Research Cytometry DNA Data Development Diagnostic Disease Environment Exposure to FCGR3B gene FDA approved Future Gene Expression Profile Genetic Transcription Goals Gut associated lymphoid tissue HIV HIV Infections HIV-1 Helper-Inducer T-Lymphocyte Histone Deacetylase Inhibitor Immune Immune Targeting Immunohistochemistry In Situ Individual Infection Interleukin-15 Laboratories Lead Lymphocyte Lymphoid Tissue Malignant Neoplasms Morbidity - disease rate Myeloid Cells Nucleic Acid Hybridization Participant Peripheral Blood Mononuclear Cell Phenotype Proviruses RNA Reporter Reporting Research Priority Residual state Resolution Sampling Source Surface T-Cell Activation T-Lymphocyte TNFRSF8 gene Techniques Technology Testing Therapeutic Therapeutic Monoclonal Antibodies Time Tissues Tonsillar Tissue Tumor Necrosis Factor Receptor Viral Viral reservoir Waxes antibody-dependent cell cytotoxicity antiretroviral therapy antitumor agent base clinical development cohort exhaustion genetic regulatory protein genome sequencing immune checkpoint improved in vitro Model inhibitor/antagonist insight lymph nodes member mortality multicatalytic endopeptidase complex next generation sequencing novel novel strategies peripheral blood purge targeted treatment therapeutic target whole genome

项目摘要

PROJECT SUMMARY/ABSTRACT Despite the ability of combination antiretroviral therapy (ART) to reduce disease-related morbidity and mortality in HIV-1 infection, viral reservoirs persist. Identification of non-viral markers associated with HIV-1 infection that can be used as a therapeutic or diagnostic target is a top research priority. Here, we demonstrate that CD30, a member of the tumor necrosis factor (TNF) receptor superfamily, is preferentially expressed on the surface of HIV-infected peripheral blood CD4+ T cells and that and HIV-1 transcriptional activity is co-localized within blood and gut tissues from participants on suppressive ART. In some individuals, HIV-1 DNA or RNA was exclusively recovered from cells expressing CD30. In further preliminary studies, ex vivo treatment with brentuximab vedotin, an FDA approved monoclonal antibody-drug conjugate (ADC) that targets CD30, resulted in up to a 4 log10 reduction in cell-associated HIV-1 DNA in samples obtained from individuals on ART. Despite these exciting data, several important questions remain. The stability of expression of CD30 and on latently infected blood and tissue-derived cells and the tissue burden and phenotypic relationships between CD30+ cells with other immune cell phenotypes is poorly understood. Even if CD30 expression waxes and wanes in infected cells, continued exposure to CD30 targeted therapies could progressively eliminate much of the reservoir. More potent reductions in HIV burden would be expected in the setting of concomitant anti-C30 therapy and latency reversal. The timing of this proposal is key as there are novel anti-CD30 therapies, such as CD16/CD30 bispecific antibodies to elicit antibody-dependent cellular cytotoxicity, in clinical development. We hypothesize that CD30 expression is stably expressed on HIV-infected, tissue-resident cells and will provide a specific therapeutic or immune target for HIV eradication. These tissue-resident cells can exist in a privileged immune environment and are likely to express markers of T cell activation and immune checkpoint/exhaustion and share features of TFH cells, an important source of persistent HIV. Results from prior cancer studies indicate that expression of key retrovrial regulatory proteins may lead to increased surface CD30 expression. However, latently infected cells may also stably express CD30, as we have observed several ART-suppressed individuals with a large majority of HIV-1 DNA recovered from CD30+ lymphocytes. Our aims are to: (1) determine if CD30 is preferentially and stably expressed on HIV-infected peripheral blood and tissue resident cells in individuals on suppressive ART treated during very early or late infection; (2) determine if ex vivo administration of brentuximab vedotin in conjunction with latency reversal will lead to significant reductions in intact cell-associated HIV DNA in PBMC from ART-suppressed individuals, and (3) determine if CD30 is continuously expressed following development of HIV latency, and define unique transcriptional signatures of HIV infected cells expressing CD30. Determining these signatures will inform on how to maximize CD30 expression on HIV infected cells and to drive future mechanistic studies.

项目概要/摘要尽管联合抗逆转录病毒疗法（ART）能够降低疾病相关的发病率和死亡率在 HIV-1 感染中，病毒库持续存在。与 HIV-1 感染相关的非病毒标记物的鉴定可用作治疗或诊断靶点是首要研究重点。在这里，我们证明了 CD30 肿瘤坏死因子 (TNF) 受体超家族的成员，优先表达于肿瘤表面 HIV 感染的外周血 CD4+ T 细胞和 HIV-1 转录活性共定位于来自接受抑制性 ART 的参与者的血液和肠道组织。在某些个体中，HIV-1 DNA 或 RNA 专门从表达 CD30 的细胞中回收。在进一步的初步研究中，离体治疗 brentuximab vedotin 是一种 FDA 批准的针对 CD30 的单克隆抗体药物偶联物 (ADC) 从接受 ART 的个体获得的样本中，细胞相关的 HIV-1 DNA 减少了 4 log10。尽管这些令人兴奋的数据仍然存在几个重要问题。 CD30及其潜在表达的稳定性受感染的血液和组织来源的细胞以及 CD30+ 之间的组织负荷和表型关系具有其他免疫细胞表型的细胞知之甚少。即使 CD30 表达在受感染的细胞，持续接触 CD30 靶向治疗可以逐渐消除大部分水库。在同时使用抗 C30 药物的情况下，预计将更有效地减少 HIV 负担治疗和潜伏期逆转。这项提议的时机很关键，因为有新的抗 CD30 疗法，例如作为 CD16/CD30 双特异性抗体，在临床开发中引发抗体依赖性细胞毒性。我们假设 CD30 表达在 HIV 感染的组织驻留细胞上稳定表达，并且将为根除艾滋病毒提供特定的治疗或免疫靶点。这些组织驻留细胞可以存在于优越的免疫环境，并且可能表达 T 细胞激活和免疫标志物检查点/耗尽并具有 TFH 细胞的特征，TFH 细胞是持续性 HIV 的重要来源。结果来自先前的癌症研究表明，关键逆转录调节蛋白的表达可能导致表面增加 CD30表达。然而，正如我们所观察到的，潜伏感染的细胞也可能稳定表达 CD30 几名 ART 抑制个体的大部分 HIV-1 DNA 从 CD30+ 淋巴细胞中恢复。我们的目标是：（1）确定CD30是否在HIV感染的外周血上优先且稳定地表达以及在早期或晚期感染期间接受抑制性 ART 治疗的个体的组织驻留细胞； (2) 确定离体给予 brentuximab vedotin 与潜伏期逆转相结合是否会导致 ART 抑制个体的 PBMC 中完整细胞相关的 HIV DNA 显着减少，以及 (3) 确定 CD30 是否在 HIV 潜伏期发展后持续表达，并定义独特的表达 CD30 的 HIV 感染细胞的转录特征。确定这些签名将告知如何最大化 HIV 感染细胞上的 CD30 表达并推动未来的机制研究。