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.

项目摘要/摘要 尽管联合抗逆转录病毒疗法(ART)能够减少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志物的鉴定 可作为治疗或诊断的靶点是研究的重中之重。在这里，我们演示CD30，一种 是肿瘤坏死因子受体超家族的成员，主要表达于肿瘤细胞表面。 HIV感染外周血中的CD4+T细胞及其与HIV-1转录活性共定位于 关于抑制艺术的参与者的血液和肠道组织。在一些人中，HIV-1DNA或RNA是 仅从表达CD30的细胞中恢复。在进一步的初步研究中，体外治疗与 FDA批准的针对CD30的单抗-药物结合物(ADC)Brentuximab vedotin的结果是 在从接受抗逆转录病毒治疗的患者身上获得的样本中，与细胞相关的艾滋病毒-1 DNA减少了高达4log10。尽管 在这些令人兴奋的数据中，仍有几个重要的问题。CD30及其潜伏期表达的稳定性 感染的血液和组织衍生细胞与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的表达大起大落 感染细胞，持续暴露于CD30靶向治疗可以逐渐消除大部分 水库。在伴随的抗C30抗体的设置中，艾滋病毒负担有望得到更有效的降低 治疗和潜伏期逆转。这一提议的时机是关键，因为有新的抗CD30疗法，如 作为CD16/CD30双特异性抗体，可诱导抗体依赖的细胞毒作用，在临床上有一定的应用价值。 我们假设CD30在HIV感染的组织驻留细胞上稳定表达 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 一种特权的免疫环境，可能表达T细胞激活和免疫的标志 TFH细胞的检查点/耗尽和共有特征，这是持续艾滋病毒的重要来源。结果来自 先前的癌症研究表明，关键的血管后调节蛋白的表达可能会导致表面的增加 CD30的表达。然而，正如我们所观察到的那样，潜伏感染的细胞也可能稳定表达CD30 几个携带绝大多数HIV-1 DNA的抗逆转录病毒治疗受抑者从CD30+淋巴细胞中恢复。 我们的目标是：(1)确定CD30是否优先和稳定地在HIV感染的外周血中表达 在感染早期或晚期对抑制ART治疗的个体和组织驻留细胞；(2) 确定体外应用Brentuximab vedotin联合逆转潜伏期是否会导致 ART抑制个体PBMC中与完整细胞相关的HIV DNA显著减少，以及(3) 确定CD30是否随着HIV潜伏期的发展而持续表达，并定义唯一的 表达CD30的HIV感染细胞的转录特征。确定这些签名将在 如何最大限度地提高HIV感染细胞上CD30的表达，并推动未来的机制研究。