MultiOMICS mechanistic identification of predictors of HIV DNA decay, restoration of immune homeostasis and HIV specific immunity in PWH with cancer receiving Immune check point therapy

接受免疫检查点治疗的癌症患者中 HIV DNA 衰变、免疫稳态恢复和 HIV 特异性免疫的预测因子的多组学机制鉴定

• 批准号: 10731665
• 负责人: Rafick Pierre Sekaly
• 金额: $ 42.08万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-03 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10731665
• 关键词: Acquired Immunodeficiency Syndrome; Address; Affect; Aftercare; Animals; Antitumor Response; Antiviral Response; Binding; Bioinformatics; Biological Assay; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; CTLA4 gene; Cancer Patient; Cell surface; Cells; Complex; DNA; Data; Data Analyses; Disease Progression; Frequencies; Genetic Transcription; HIV; Heterogeneity; Homeostasis; Immune; Immune System Diseases; Immune response; Immune system; Immunity; Immunologics; Immunology; Immunology procedure; Impairment; Individual; Inflammation Mediators; Inflammatory; Inflammatory Response; Innate Immune Response; Interruption; Intervention; Kaposi Sarcoma; Knowledge; Lead; Maintenance; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Monoclonal Antibodies; Natural Immunity; Non-Hodgkin' s Lymphoma; Outcome; PD-1 blockade; PD-1/PD-L1; PD-L1 blockade; Participant; Patients; Persons; Plasma; Predisposition; Proteins; RNA; Rejuvenation; Research; Role; SIV; Shapes; Signal Transduction; Subgroup; System; T cell response; T-Lymphocyte; Testing; Therapeutic; Tumor Promotion; Validation; Viral; Viral reservoir; Viremia; Work; adaptive immune response; adaptive immunity; anti-PD-1; anti-PD1 antibodies; antiretroviral therapy; checkpoint therapy; chemokine; clinical trial protocol; clinically significant; cohort; commensal bacteria; cytokine; data integration; effector T cell; exhaust; exhaustion; immune checkpoint; immune checkpoint blockade; immune function; immune reconstitution; immunological intervention; immunoregulation; improved; in vivo; inflammatory milieu; innate immune mechanisms; integration site; metabolome; microbiome; mortality; multiple omics; pathogen; post intervention; programmed cell death ligand 1; programmed cell death protein 1; programs; recruit; restoration; treatment response; tumor; tumor microenvironment; viral DNA; viral RNA

ABSTRACT – Project 2 The overall objective of this Program project application is to generate a comprehensive understanding of the complex host-pathogen interactions critical for HIV reservoir persistence and decay post-PD-1/PD-L1 signaling blockade by monoclonal antibodies in HIV-cancer participants. The knowledge gap we address in Project 2 is how the maintenance of HIV reservoirs by different systemic inflammatory mediators (circulating microbiome, host/non-host metabolites and cytokines/chemokines) in the participants can modulate HIV reservoir persistence and its susceptibility to the immune intervention (decay vs non-decay). We will also address how this initial virological and inflammatory milieu can lead to a broad impact of the intervention in the immune responses. In yet unpublished data we demonstrate that metabolites downstream of commensal bacteria can impact on the magnitude of the HIV reservoir, and HIV integration dynamics and by modulating cell fate (innate and adaptive, importantly CD4 T cells, the major HIV reservoir), this milieu can influence the responsiveness to the immune intervention. We have recruited 3 cohorts of PWH also affected by cancers to help us to address these knowledge gaps. In this proposal we will apply state of the art virological assays and integrated multi-OMICs immunological assays to test the hypothesis that distinct microbiomes and metabolomes prevalent in HIV- cancer participants pre-immune intervention with aPD-1/PD-L1 drive the different virological outcomes (vDNA and vRNA) post-intervention and immunological (innate and adaptive immunity) readouts as early as day 1 post-treatment. The specific objectives of Project 2 are to i) evaluate the quantity and the quality of the HIV reservoir pre-immune intervention and its modulation post-immune intervention; ii) to evaluate how the immune intervention reverse immune dysfunction (innate and adaptive); and iii) to evaluate how the host circulating milieu pre-immune intervention, based on microbiome and metabolites composition, is associated with the reservoir dynamics and immune responses post-immune intervention in HIV- cancer participants from the 3 different cohorts. The proposed research builds on our expertise with HIV-cancer cohorts and established systems immunology approaches to deeply interrogate HIV reservoirs and immune function. The ability to immune intervene in these cohorts with different strategies targeting the PD-1/PD-L1 signaling gives us the unique opportunity to modulate reservoir persistence and immune function. We will work with the Bioinformatic Core to perform data analysis and integration across all 3 projects of this program and we are confident that the research proposed in Project 2 will lead to important discoveries regarding immune regulation of HIV reservoirs and immune dysfunction in HIV-cancer cohorts. It is our objective to turn these discoveries into better defined clinical trial protocols to advance research towards a cure for cancer-HIV participants and also extend it to PWH without cancer.

摘要-项目2