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Targeting HIV persistence in CD4+ T memory stem cells

靶向 CD4 T 记忆干细胞中的 HIV 持久性

基本信息

批准号：
9321252
负责人：
Viviana A Simon
金额：
$ 42.38万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-10 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9321252
关键词：
AIDS/HIV problem Agreement Anti-Retroviral Agents Antiviral Agents Antiviral Therapy Architecture Biology CD4 Positive T Lymphocytes Cell Culture Techniques Cell Lineage Cells Characteristics Collaborations Cytometry DNA Data Disease Engineering Event Frequencies Generations Genetic Genetic Transcription Genome Genomics Goals HDAC1 gene HIV HIV Infections HIV Seropositivity Highly Active Antiretroviral Therapy Human IL2 gene Immune Immunologic Surveillance Infection Infection Control Integration Host Factors Interleukin-15 Intervention Knowledge Laboratories Life Maintenance Measures Memory Modeling Molecular Molecular Probes Nuclear Oligonucleotides Outcome Pathogenesis Pathway interactions Patients Persons Physiological Play Population Proliferating Property Proteins Proteome Proteomics Proviruses Reporter Research Reverse Transcription Role SIV Seeds Signal Transduction Source Stem cells T memory cell T-Lymphocyte Testing Therapeutic Time Viral Virus Virus Diseases base cytokine genetic makeup in vivo inhibitor/antagonist innovation memory CD4 T lymphocyte novel offspring programs public health relevance purge research study self-renewal stem volunteer

项目摘要

DESCRIPTION (provided by applicant): Eliminating HIV persistence is an obligated step to curing HIV/AIDS disease. Indeed, life-long highly active antiretroviral therapy is required since current antiviral drugs fail to eliminate the virus from HIV-infected patients. Despite intensive research there are no effective strategies to eliminate latent, transcriptionally silent HIV proviruses from HIV infected patients with well-controlled HIV infection. Emerging evidence suggest that CD4+ T memory stem cells (TSCM), the least differentiated of all CD4+ T cell memory populations, support HIV infection. There remains, however, a fundamental gap in our knowledge regarding the mechanisms and the extent of the impact of CD4+ T cells with stem like properties (TSMC) on establishment of HIV latency and persistence. Our preliminary data suggests that TSCM are fundamentally different from other CD4+ T memory cells. Since stem cells can renew and generate progeny cells for prolonged periods, we hypothesize that infected TSCM persist, maintain and seed CD4 T cells carrying latent proviruses. We will use mass-cytometry, 3D-FISH, proteomics and genomics to probe for the molecular mechanisms of latency establishment and maintenance specific for primary human CD4 T stem cells. We will define correlates of abortive, silent and productive infections in CD4+ TSCM, define the cellular programs specific for HIV persistence in CD4+ TSCM and probe for the CD4+ TSCM reservoir in HIV positive patients with spontaneous or HAART-assisted control of HIV infection. We will test to what extent a small number of integrations can seed the reservoir carrying the same latent provirus over multiple cell generations. Understanding the molecular mechanisms underlying latency establishment and maintenance in CD4+ TSCM is essential to develop targeted interventions aimed at shrinking and purging HIV persistence in CD4+ TSCM.