Delaney AIDS Research Enterprise to Cure HIV

德莱尼艾滋病研究企业治愈艾滋病毒

• 批准号: 10626936
• 负责人: STEVEN Grant DEEKS
• 金额: $ 545.24万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-16 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10626936
• 关键词: Acceleration; Acquired Immunodeficiency Syndrome; Address; Aftercare; Animal Model; Anti-Retroviral Agents; Antigens; Apoptotic; BCL1 Oncogene; Binding; Biological; CD8-Positive T-Lymphocytes; Cell Death; Cell Survival; Cells; Cessation of life; Clinical; Clinical Trials; Clinical Trials Design; Cytomegalovirus Vaccines; Development; Disease remission; Event; Frequencies; Future; Genetic Transcription; Goals; Growth; HIV; HIV Infections; Helper-Inducer T-Lymphocyte; Human; Immune; Immune Evasion; Immune response; Immune system; Immunologics; Immunotherapy; In Vitro; Individual; Infection; Innate Immune Response; Intercept; Interruption; Investments; Lymphoid Tissue; Mediating; Mission; Modeling; Monkeys; Nature; Pathway interactions; Persons; Pharmaceutical Preparations; Population; Predisposition; Proliferating; Proteins; Proviruses; Recrudescences; Regimen; Research; Research Design; Research Personnel; Residual state; Resistance; Resources; SIV; Sampling; Series; Signal Transduction; T cell response; T-Lymphocyte; Testing; Therapeutic; Viral; Viral Antigens; Viral Proteins; Viremia; Virus; Work; acute infection; adaptive immune response; antagonist; antiretroviral therapy; cell killing; cohort; collaboratory; combinatorial; design; humanized mouse; in vitro Model; in vivo; meetings; member; mimetics; mouse model; nonhuman primate; preclinical development; prevent; programs; response; therapy development; treatment optimization; viral RNA; viral rebound

PROJECT SUMMARY/ABSTRACT The goals of the DARE Collaboratory are to develop a viable combination regimen that reduces the rebound- competent HIV/SIV reservoir during antiretroviral therapy (ART) and/or induces durable control of HIV/SIV in the absence of therapy. Our proposed work is based on two observations made our group. First, we found that virus- specific CD8+ T cells contribute to control of the virus at steady-state. These cells, however, have limited effect during and immediately post-ART. We believe and will seek to prove that effective remission strategies will require organization of a robust innate and adaptive immune response during the earliest stages of virus rebound, effectively intercepting and suppressing viral rebound prior to the massive systemic growth of SIV/HIV that overwhelms, damages and/or evades the immune system. Second, we and others have found that despite virus expression during ART (either naturally or in response to a latency reversal agent), the frequency of infected cells remains stable. We have found that infected cells are relatively resistant to cell death programs. We will develop therapies that render these cells to host-mediated clearance mechanisms, thus resulting in their reduction and perhaps elimination. To achieve our goals, we will (1) characterize in people transcriptionally active cells and proliferating infected cells, focusing on identifying mechanisms for persistence, (2) define in people the earliest immunologic and virologic events post-interruption of ART, focusing on post-treatment controllers, (3) develop in non-human primates (NHPs) a combination regimen that targets the reactivating virus during the immediate post-ART period and results in sustained control at set-point and (4) develop in vitro and in animal models therapies that render the reservoir more susceptible to death through the activation of intrinsic (cellular) and/or extrinsic (virus-specific) pro-apoptotic pathways. This work will leverage our deep investment in (1) the optimization of the SIV NHP model and a humanized mouse model, both developed specifically to support the types of studies we will pursue, (2) the development of a robust clinical cohort (SCOPE) designed to support intensive, biologic studies of people living with HIV (PWH), and (3) the implementation and conduct of several clinical trials designed in part to test our hypotheses in people and from which samples will be made available to our team for ex vivo studies. We anticipate meeting the following milestones and deliverables: (1) definition of the active reservoir in lymphoid tissues from SIV-infected monkeys and HIV-infected humans on effective ART, (2) determination of whether reservoir cells are resistant to intrinsic and extrinsic cell killing, (3) development of a viable and translatable remission strategy in NHPs, and (4) identification and pre-clinical development of interventions aimed at enhancing the cell death, either by making cells more susceptible to cell death and/or by optimizing the efficacy of the virus-specific T cell response.

项目总结/文摘

项目成果

Viral competition assay to assess the role of HIV-1 proteins in immune evasion.

• DOI: 10.1016/j.xpro.2022.102025
• 发表时间: 2023-03-17
• 期刊: STAR PROTOCOLS
• 作者: Duette, Gabriel;Cronin, Samantha;Kelleher, Anthony D.;Palmer, Sarah
• 通讯作者: Palmer, Sarah

Unequal distribution of genetically-intact HIV-1 proviruses in cells expressing the immune checkpoint markers PD-1 and/or CTLA-4.

• DOI: 10.3389/fimmu.2023.1064346
• 发表时间: 2023
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Fisher K;Schlub TE;Boyer Z;Rasmussen TA;Rhodes A;Hoh R;Hecht FM;Deeks SG;Lewin SR;Palmer S
• 通讯作者: Palmer S

Evolving Strategies to Eliminate the CD4 T Cells HIV Viral Reservoir via CAR T Cell Immunotherapy.

• DOI: 10.3389/fimmu.2022.873701
• 发表时间: 2022
• 期刊: Frontiers in immunology
• 影响因子: 7.3

Markers of Immune Activation and Inflammation Are Associated with Higher Levels of Genetically-Intact HIV in HIV-HBV Co-Infected Individuals.

• DOI: 10.1128/jvi.00588-22
• 发表时间: 2022-08-24
• 期刊: JOURNAL OF VIROLOGY
• 影响因子: 5.4
• 作者: Wang, Xiao Qian;Zerbato, Jennifer M.;Avihingsanon, Anchalee;Fisher, Katie;Schlub, Timothy;Rhodes, Ajantha;Audsley, Jennifer;Singh, Kasha P.;Zhao, Wei;Lewin, Sharon R.;Palmer, Sarah
• 通讯作者: Palmer, Sarah

Combination Immune Checkpoint Blockade Enhances IL-2 and CD107a Production from HIV-Specific T Cells Ex Vivo in People Living with HIV on Antiretroviral Therapy.

• DOI: 10.4049/jimmunol.2100367
• 发表时间: 2022-01-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Chiu CY;Chang JJ;Dantanarayana AI;Solomon A;Evans VA;Pascoe R;Gubser C;Trautman L;Fromentin R;Chomont N;McMahon JH;Cameron PU;Rasmussen TA;Lewin SR
• 通讯作者: Lewin SR