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。艾滋病毒活载体疫苗是一种很有前途的手段，可引发艾滋病毒特异性细胞和体液免疫反应。促成对活载体疫苗产生有效的艾滋病毒特异性免疫反应的因素仍未完全确定。目前提出的主要假设是，HIV活载体疫苗形成的假病毒粒子通过在局部淋巴结中递送颗粒抗原来增强细胞和体液免疫反应。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细胞和体液对HIV抗原的反应。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。Aim 1中的实验将比较能够产生假病毒粒子的活载体与缺乏产生假病毒粒子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粒子有可能以天然构象呈现包膜糖蛋白，并产生有效结合和中和HIV颗粒的抗体。在第二部分中，我们将分析Vpu在增强Gag-Env活载体免疫原性方面的潜在作用。Aim 3的实验将验证假病毒载体产生抗原的假设，该抗原更有效地到达区域淋巴组织。总之，这些实验将为假病毒粒子在活载体免疫后产生hiv特异性免疫反应中的作用提供重要见解。

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.