Targeting Non Viral Markers of HIV Persistence

针对 HIV 持续存在的非病毒标志物

• 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
• 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

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.

项目总结/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，病毒宿主持续存在。鉴定与HIV-1感染相关的非病毒标志物， 可用作治疗或诊断靶点是研究的首要任务。在这里，我们证明了CD 30， 肿瘤坏死因子（TNF）受体超家族成员，优先表达于 HIV感染的外周血CD 4 + T细胞与HIV-1转录活性共定位于 在一些个体中，HIV-1 DNA或RNA被检测到， 仅从表达CD 30的细胞中回收。在进一步的初步研究中，使用 维布妥昔单抗是一种FDA批准的靶向CD 30的单克隆抗体-药物偶联物（ADC）， 在从接受抗逆转录病毒治疗的个体获得的样本中，细胞相关HIV-1 DNA减少高达4 log 10。 这些令人兴奋的数据，几个重要的问题仍然存在。CD 30表达的稳定性和潜伏性 感染的血液和组织来源的细胞以及组织负荷和CD 30+之间的表型关系 细胞与其他免疫细胞表型的关系知之甚少。即使CD 30的表达有增有减， 感染的细胞，持续暴露于CD 30靶向治疗可以逐渐消除大部分的 水库在伴随抗C30的情况下，预计HIV负荷的降低更有效 治疗和潜伏期逆转。这项建议的时机是关键，因为有新的抗CD 30疗法，如 作为CD 16/CD 30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CD 30在HIV感染的组织驻留细胞上稳定表达， 将为HIV根除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 一个特权的免疫环境，并可能表达T细胞活化和免疫的标志物， 检查点/耗尽和TFH细胞的共同特征，这是持续性HIV的重要来源。结果 先前的癌症研究表明，关键的逆转录病毒调节蛋白的表达可能导致细胞表面的增加， CD 30表达。然而，正如我们所观察到的，潜伏感染的细胞也可以稳定表达CD 30 几个ART抑制的个体，其中大部分HIV-1 DNA从CD 30+淋巴细胞中回收。 我们的目的是：（1）确定CD 30是否在HIV感染者外周血中优先稳定表达 以及在极早期或晚期感染期间接受抑制性ART治疗的个体中的组织驻留细胞;（2） 确定维布妥昔单抗离体给药联合潜伏期逆转是否会导致 ART抑制个体PBMC中完整细胞相关HIV DNA显著减少，和（3） 确定CD 30是否在HIV潜伏期发展后持续表达，并定义独特的 表达CD 30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CD 30表达，并推动未来的机制研究。