Immunoprophylaxis By Gene Transfer: Shortcut To An HIV Vaccine

描述（由申请人提供）：对安全有效的HIV疫苗的需求是无可争议的。仅在2011年，就有近200万人死于与艾滋病有关的原因，同时有250万人新感染艾滋病毒。传统的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。选择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）载体中。当注射（肌内）到宿主体内时，载体指导抗体的体内产生，导致针对HIV的血清中和活性。换言之，抗体是由肌纤维而不是浆细胞产生的。在拟议的研究中，我们将通过使用一组新发现的具有广泛和有效的抗HIV活性的人单克隆抗体构建rAAV载体来扩展我们以前的工作。这些抗体是理想的候选物，因为它们具有在非常可实现的浓度下中和广泛的HIV分离株的潜力（目标1a）。同样，我们将基于CD 4-IgG融合蛋白产生新形式的抗体样分子，旨在抑制HIV进入，并在rAAV载体和动物模型中测试这些分子（Aim 1b）。在一个单独的项目（目标2）中，我们将开发一类基于白蛋白融合蛋白的新型HIV进入抑制剂，并同样在rAAV载体和动物模型中测试这些抑制剂。最后，我们将利用最近描述的诱导型半胱天冬酶系统来开发一种“安全开关”，该开关将杀死转导的细胞，从而在观察到意外效应的罕见情况下消除转基因表达（目的3）。

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).