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.

项目摘要/摘要尽管有抗逆转录病毒疗法（ART）的能力降低与疾病相关的发病率和死亡率在HIV-1感染中，病毒储层持续存在。鉴定与HIV-1感染相关的非病毒标记可以用作治疗或诊断目标是最佳研究优先事项。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在 HIV感染的外周血CD4+ T细胞以及HIV-1转录活性在共定位参与者抑制艺术的血液和肠道组织。在某些人中，HIV-1 DNA或RNA是仅从表达CD30的细胞中恢复。在进一步的初步研究中，与 Brentuximab vedotin是FDA批准的靶向CD30的单克隆抗体 - 药物结合物（ADC）在从ART的个体获得的样品中，在细胞相关的HIV-1 DNA中最多可减少4 log10。尽管这些令人兴奋的数据，仍然存在几个重要问题。 CD30和潜在的表达的稳定性感染的血液和组织衍生的细胞以及CD30+之间的组织负担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表达蜡和衰竭受感染的细胞，持续暴露于CD30靶向疗法可以逐步消除大部分水库。在伴随抗C30的情况下，预计艾滋病毒负担会增加艾滋病毒负担治疗和潜伏期逆转。该提案的时机是关键，因为有新型的抗CD30疗法，例如作为临床发育中的CD16/CD30双特异性抗体引起抗体依赖性细胞毒性。我们假设CD30表达在HIV感染，组织居民细胞和将为消除HIV提供特定的治疗或免疫靶标。这些居住的细胞可以存在于特权免疫环境，可能表达T细胞激活和免疫的标记检查点/精疲力尽和共享TFH细胞的特征，TFH细胞是持续HIV的重要来源。结果先前的癌症研究表明，关键逆转调节蛋白的表达可能导致表面增加 CD30表达。但是，如我们观察到从CD30+淋巴细胞中回收的几个具有大部分HIV-1 DNA的Art抑制个体。我们的目的是：（1）确定在HIV感染的外周血上优先且稳定地表达CD30是否在很早或晚期感染期间接受抑制艺术的个体中的组织细胞；（2）确定brentuximab vedotin与潜伏期逆转是否会导致体内给药是否会导致来自Art抑制个体的PBMC中与细胞相关的完整相关HIV DNA的显着降低，（3）确定在艾滋病毒潜伏期发展后是否连续表达CD30，并定义独特表达CD30的HIV感染细胞的转录特征。确定这些签名将告知如何在HIV感染细胞上最大化CD30表达并推动未来的机械研究。