Immunoprophylaxis By Gene Transfer: Shortcut To An HIV Vaccine

通过基因转移进行免疫预防：艾滋病毒疫苗的捷径

• 批准号: 8721334
• 负责人: Philip R Johnson
• 金额: $ 114.71万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-14 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8721334
• 关键词: Acquired Immunodeficiency Syndrome; Albumins; Animal Model; Antibodies; Antibody Formation; Antigens; Binding; Biological Models; Bypass; CCR5 gene; Caspase; Caspase Gene; Chimeric Proteins; Engineering; Gene Transfer; Genes; HIV; HIV Entry Inhibitors; HIV Envelope Protein gp120; HIV Infections; HIV vaccine; Half-Life; Human; Human immunodeficiency virus test; Immune response; Immunity; Immunoglobulin A; Immunoglobulin G; Membrane Fusion; Modeling; Monkeys; Mus; Pathway interactions; Peptides; Plasma Cells; Property; Recombinant adeno-associated virus (rAAV); Research; Research Project Grants; Risk; SIV; Safety; Serum; Site; Suicide; System; Technology; Testing; Transgenes; Vaccines; Veins; Virulent; Virus; Work; adeno-associated viral vector; base; cellular transduction; design; gp160; human monoclonal antibodies; immunogenicity; immunoprophylaxis; in vivo; inhibitor/antagonist; killings; novel; novel strategies; prevent; public health relevance; transgene expression; vaccine candidate; vaccine development; vector

DESCRIPTION (provided by applicant): The need for a safe and effective HIV vaccine is undisputed. In 2011 alone, nearly 2 million people died from AIDS related causes, while 2.5 million people were newly infected with HIV. Traditional approaches have failed to produce an efficacious HIV vaccine, and near-term prospects for a vaccine remain uncertain. We have taken a different approach to HIV immunoprophylaxis that completely bypasses the adaptive immune response. One selects an antibody (or antibody-like molecule) with the desired neutralizing properties, clones the antibody gene, and then inserts it into a recombinant adeno-associated virus (rAAV) vector. When injected (intramuscularly) into a host, the vector directs in vivo production of the antibody that leads to serum neutralizing activity against HIV. In other words, antibodies are produced by myofibers instead of plasma cells. In the proposed research, we will extend our previous work by constructing rAAV vectors using a new set of recently discovered human monoclonal antibodies with broad and potent activity against HIV. Such antibodies are ideal candidates because they have the potential to neutralize a wide range of HIV isolates at very achievable concentrations (Aim 1a). In the same vein, we will generate new forms of antibody-like molecules based on CD4-IgG fusion proteins designed to inhibit HIV entry, and test these in rAAV vectors and animal models (Aim 1b). In a separate project (Aim 2), we will develop a novel class of HIV entry inhibitors based on albumin fusion proteins, and likewise, test these in rAAV vectors and animal models. Finally, we will exploit a recently described inducible caspase system to develop a "safety switch" that will kill transduced cells, thereby eliminating transgene expression for rare situations where unexpected effects are observed (Aim 3).

描述(由申请人提供)：安全有效的艾滋病毒疫苗的必要性是毋庸置疑的。仅在2011年，就有近200万人死于艾滋病相关原因，而250万人新感染了艾滋病毒。传统方法未能生产出有效的艾滋病毒疫苗，疫苗的近期前景仍然不确定。我们采取了一种完全绕过适应性免疫反应的不同的艾滋病毒免疫预防方法。人们选择一种具有所需中和特性的抗体(或抗体样分子)，克隆抗体基因，然后将其插入重组腺相关病毒(RAAV)载体。当(肌肉内)注射到宿主体内时，该载体引导体内产生抗体，从而导致血清中和抗艾滋病毒的活性。换句话说，抗体是由肌纤维而不是浆细胞产生的。在拟议的研究中，我们将扩展我们之前的工作，使用一组新发现的具有广泛和有效的抗HIV活性的人类单抗构建rAAV载体。这种抗体是理想的候选抗体，因为它们有可能在非常容易达到的浓度下中和多种艾滋病毒分离株(目标1a)。同样，我们将基于旨在抑制艾滋病毒进入的CD4-IgG融合蛋白，产生新形式的抗体样分子，并在rAAV载体和动物模型中进行测试(目标1b)。在另一个单独的项目(目标2)中，我们将开发一类基于白蛋白融合蛋白的新型艾滋病毒进入抑制剂，并同样在rAAV载体和动物模型中测试这些药物。最后，我们将利用最近描述的可诱导caspase系统来开发一种“安全开关”，它将杀死转导细胞，从而在观察到意外效果的罕见情况下消除转基因表达(目标3)。