Pseudovirion Formation by Live Vector HIV Vaccines

描述（由申请人提供）：开发安全有效的艾滋病毒疫苗是当务之急。活载体HIV疫苗代表了引发HIV特异性细胞和体液免疫应答的有希望的手段。导致对活载体疫苗产生强有力的艾滋病毒特异性免疫应答的因素仍然没有完全确定。目前的建议的主要假设是，假病毒颗粒形成活载体HIV疫苗增强细胞和体液免疫反应，通过交付颗粒抗原呈递在区域淋巴结。我们的实验室最近证明，与缺乏颗粒形成的匹配载体相比，金丝雀痘载体产生的假病毒粒子增加了对HIV抗原的细胞和体液反应。本提案中描述的实验将确定该特性是否适用于MVA和腺病毒载体。目的1中的实验将比较能够产生假病毒体的活载体与缺乏产生假病毒体的能力的匹配载体的免疫原性。特别令人感兴趣的是从活HIV疫苗载体表达的假病毒体以天然构象呈递包膜糖蛋白并产生将有效结合和中和HIV颗粒的抗体的潜力。在目的2中，将分析Vpu在增强活Gag-Env载体的免疫原性中的潜在作用。目的3中的实验将检验假病毒体感受态载体产生更有效地到达区域淋巴组织的抗原的假设。总之，这些实验将提供重要的见解假病毒粒子在产生HIV特异性免疫反应后活载体免疫的作用。

DESCRIPTION (provided by applicant): The development of a safe and effective HIV vaccine is an urgent priority. Live vector HIV vaccines represent a promising means of eliciting HIV-specific cellular and humoral immune responses. The factors that contribute to a potent HIV-specific immune response to live vector vaccines remain incompletely defined. The major hypothesis of the current proposal is that pseudovirion particle formation by live vector HIV vaccines enhances cellular and humoral immune responses through delivery of particulate antigen for antigen presentation in regional lymph nodes. Our laboratory has recently demonstrated that pseudovirion production by a canarypox vector increases cellular and humoral responses to HIV antigens by comparison with a matched vector that is deficient in particle formation. Experiments described in this proposal will determine if this property is applicable to MVA and adenovirus vectors. Experiments in Aim 1 will compare the immunogenicity of live vectors that are able to produce pseudovirions with matched vectors that lack the capacity to make pseudovirions. Of particular interest is the potential for pseudovirions expressed from live HIV vaccine vectors to present envelope glycoproteins in a native conformation and generate antibodies that will effectively bind and neutralize HIV particles. In Aim 2, the potential role of Vpu in enhancing immunogenicity of live Gag-Env vectors will be analyzed. Experiments in Aim 3 will test the hypothesis that pseudovirion-competent vectors produce antigen that more efficiently reaches regional lymphoid tissue. Together, these experiments will provide important insights into the role of pseudovirions in generating HIV-specific immune responses following live vector immunization.