An AAV Approach to Treating HIV

治疗 HIV 的 AAV 方法

• 批准号: 9292034
• 负责人: Matthew Ryan Gardner
• 金额: $ 5.92万
• 依托单位: SCRIPPS FLORIDA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9292034
• 关键词: Address; Affinity; Animals; Anti-Retroviral Agents; Antibodies; Antibody Therapy; Antibody titer measurement; Binding Sites; Biological Assay; CCR5 gene; CXCR4 gene; Cell surface; Data; Dependovirus; Detection; Disease; Dose; Fellowship; Gene Transduction Agent; Goals; HIV; HIV Entry Inhibitors; HIV vaccine; HIV-1; HIV-2; Human; Immune response; Individual; Infection; Injection of therapeutic agent; Innate Immune Response; Interferons; Intravenous; Macaca; Macaca mulatta; Measurable; MicroRNAs; Pathway interactions; Pharmacotherapy; Positioning Attribute; Principal Investigator; Production; Proteins; Publishing; Regulation; Research; Research Training; Resistance; SIV; Safety; Testing; Time; Transgenes; Unspecified or Sulfate Ion Sulfates; Viral; Viral Load result; Viremia; Virus; Work; World Health Organization; adeno-associated viral vector; antiretroviral therapy; base; experimental study; gene therapy; humanized mouse; immunogenic; improved; in vitro Assay; in vivo; inhibitor/antagonist; neutralizing antibody; peptidomimetics; receptor; response; simian human immunodeficiency virus; transgene expression; viral RNA; viral rebound

PROJECT SUMMARY We have recently published our research that characterizes eCD4-Ig. eCD4-Ig is an antibody-like HIV entry inhibitor that fuses a sulfated CCR5-mimetic peptide to the C-terminus of CD4-Ig. Based on neutralization assay data, eCD4-Ig is broader than and equally potent as some of the best described HIV-1 broadly neutralizing antibodies to date. eCD4-Ig neutralized all isolates tested including 38 HIV-1 isolates resistant to 3BNC117 or NIH45-46, HIV-2, SIVmac239, SIVmac251, and isolates that use CXCR4 as their coreceptor. The addition of the CCR5-mimetic peptide allowed eCD4-Ig to have higher affinity for cell surface-expressed HIV-1 Env and also limited viral enhancement caused by sub-neutralizing levels of CD4-Ig. Using adeno-associated virus (AAV) vectors, we have shown that a rhesus form of eCD4-Ig can be expressed in four rhesus macaques for over one year with no harm to the animals. The rh- eCD4-Ig protein titers were at levels that protected all four macaques from multiple SHIV-AD8 challenges up to 16-times the AID50 (Animal Infectious Dose 50). We did observe a measurable anti- transgene response to the expressed rh-eCD4-Ig protein, but the response was not near the levels seen against AAV-delivered HIV-1 antibodies. Yet, even a relatively modest immune response to the delivered transgene can limit the inhibitor’s efficacy in vivo. With these encouraging data, this proposal seeks to answer two main questions: (1) Can AAV-expressed eCD4-Ig be used as a therapy to maintain viral suppression in SHIV infected macaques? (2) Can interferon-induced miRNAs regulate transgene expression from AAV vectors to limit the host immune response to the transgene? With the primary goal of using eCD4-Ig as an alternative to antiretroviral therapies, answering these two questions will continue to build on the safety and efficacy of AAV-delivered eCD4-Ig as well as realizing the complete potential of AAV vectors used for gene therapy.

项目总结