EVALUATION OF INHIBITION OF SHIV REPLICATION BY SIRNA VECTORS

SIRNA 载体对 SHIV 复制抑制的评价

• 批准号: 7562014
• 负责人: Stephen E. Braun
• 金额: $ 5.2万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7562014
• 关键词: Acquired Immunodeficiency Syndrome; Address; Clinical Trials; Collaborations; Computer Retrieval of Information on Scientific Projects Database; Evaluation; Experimental Models; Funding; Generations; Genes; Grant; HIV; HIV-1; Hematopoietic stem cells; Human; Immune; Institution; Life; Macaca; Modeling; Numbers; Polymerase; Reporting; Research; Research Personnel; Resources; Site; Small Interfering RNA; Source; Stem cells; Transfection; United States National Institutes of Health; Viral; Virus; gene therapy; in vivo; nonhuman primate; promoter; reconstitution; research study; simian human immunodeficiency virus; small hairpin RNA; vector

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Introduction of genes able to inhibit HIV replication into hematopoietic stem cells offers the potential for long-lived immune reconstitution. However, multiple ethical and practical considerations significantly constrain the ability to address basic questions regarding stem cell gene therapy for AIDS in human clinical trials. Experiments in nonhuman primates therefore offer the opportunity to rigorously address these issues in an in vivo experimental model. A number of recent reports have highlighted the potential utility of small interfering RNA (siRNA) molecules to inhibit viral replication. In collaboration with J. Rossi, we initiated inhibition studies of various SHIV strains with siRNA targeting Tat and Rev. We obtained two siRNA (one targeting both Tat and Rev and the other targeting only Rev) and a control sequence, each transcriptionally regulated by the polymerase III promoter U6. Using transient transfection both si(I) and si(II) strongly inhibited HIV-1 (as previously shown), SHIV 89.6p and SHIV Hxbc2 3.2P (viruses with homologous envelopes). Using a second generation construct expressing the site I and site II interfering RNAs as a hairpin sequence (shRNA) has demonstrated even more potent inhibition of SHIV replication by over 1000-fold. These encouraging results support further studies of the utility of siRNA to inhibit SHIV replication in vivo in the macaque model.

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