Development of Molecular Adjuvants for Therapeutic HIV-1 Vaccines

描述（由申请人提供）：使用抗逆转录病毒疗法，即高活性抗逆转录病毒疗法（HAART）治疗HIV-1的进展目前受到终身用药的成本和毒性的限制。已经提出了一种创新的治疗策略，以增强感染HIV-1疫苗的患者的免疫系统，并有助于限制HAART的使用。然而，治疗性疫苗接种的概念意味着宿主免疫系统在接种疫苗后仍然有能力引发免疫反应。患有HIV-1感染的患者通常表现出由CD4+ T细胞的丧失引起的免疫防御受损，而CD4+ T细胞对于建立细胞介导和抗体（Ab）介导的免疫反应至关重要。为了克服当前免疫治疗性HIV-1疫苗开发的这一挑战，我们建议在疫苗接种的初始和增强阶段添加CD40配体（肿瘤坏死因子超家族（TNFSF）分子的成员），以增加缺乏CD4+ T细胞帮助的免疫功能低下宿主的抗病毒应答。最近在小鼠系统中的研究表明，CD4+ T细胞通过与树突状细胞（DCs）的相互作用来帮助抗病毒CD8+细胞毒性T淋巴细胞（CTL）反应。此外，CD40L和CD40在dc上的结扎可以取代或绕过CD4+ T细胞的帮助。因此，我们假设将CD40L作为分子佐剂与疫苗联合使用可能代表一种新策略，可以在CD4+ T细胞缺陷状态（如HIV-1感染）中诱导有效的抗病毒CTL和Ab反应。我们有两个特定的目的：1)在CD4+ T细胞缺失的小鼠模型中，确定在免疫启动和增强阶段添加CD40L作为分子佐剂的异源DNA启动- alvac增强疫苗方法是否可以在缺乏CD4+ T细胞帮助的情况下改善对vCP1452（一种目前许可的ALVAC-HIV疫苗）免疫的hiv -1特异性CTL和Ab反应；2)在CD4+ T细胞功能受损的老年小鼠中，确定DNA引物- alvac增强策略在接种启动期和增强期均添加CD40L作为分子佐剂，是否也能提高HIV疫苗vCP1452的免疫原性。该建议在使用分子佐剂绕过CD4+ T细胞帮助开发针对免疫功能低下患者的治疗性HIV-1疫苗方面具有创新性。这项研究的长期目标是开发一种新的HIV-1疫苗治疗配方，与分子佐剂联合使用，在免疫功能低下的HIV-1感染宿主中诱导更有效和持久的CTL和Ab反应。简单地说：这项研究将在小鼠模型中开发和评估一种新的治疗性HIV疫苗方案，该方案在缺乏CD4+ T帮助的情况下大致模仿人类艾滋病的加速形式。从这项研究中获得的数据将为开发针对感染艾滋病毒/艾滋病的年轻人和老年人的治疗性疫苗提供关键信息。

DESCRIPTION (provided by applicant): The advances seen with the use of anti-retroviral treatment, known as highly active anti-retroviral therapy (HAART), against HIV-1 are limited today by the cost and toxicity of lifelong administration of the drugs. An innovative therapeutic strategy has been proposed to boost the immune system of infected patients with HIV-1 vaccines and to help limit the use of HAART. However, the concept of therapeutic vaccination implies that the host immune system is still competent for eliciting an immune response after vaccination. Patients suffering from HIV-1 infection usually exhibit impaired immune defenses caused by the loss of the CD4+ T cells that are essential for mounting both the cell-mediated and antibody (Ab)-mediated immune responses. To overcome this challenge for current immunotherapeutic HIV-1 vaccine development, we propose to develop a heterologous prime-boost vaccine approach with the addition of CD40 ligand, a member of the tumor necrosis factor superfamily (TNFSF) of co-stimulatory molecules, in both the prime and boost phases of vaccination to increase antiviral responses in an immunocompromised host with deficiency of CD4+ T cell help. Recent studies in murine systems have demonstrated that CD4+ T cell help is required for antiviral CD8+ cytotoxic T lymphocyte (CTL) response through interactions with dendritic cells (DCs). Furthermore, the help from CD4+ T cells can be replaced or bypassed by ligation of CD40L with CD40 on DCs. We, therefore, hypothesize that employing CD40L as a molecular adjuvant in combination with vaccines may represent a novel strategy to induce potent antiviral CTL and Ab responses in CD4+ T cell-deficient states such as HIV-1 infection. We have two specific aims: 1) determine whether a heterologous DNA prime-ALVAC boost vaccine approach with the addition of CD40L as a molecular adjuvant in both the prime and boost phases of vaccination can improve HIV-1-specific CTL and Ab responses to vCP1452 (a currently licensed ALVAC-HIV vaccine) immunization in the absence of CD4+ T cell help in a CD4+ T cell-depleted murine model; 2) determine whether the DNA prime-ALVAC boost strategy with the addition of CD40L as a molecular adjuvant in both the prime and boost phases of vaccination can also improve the HIV vaccine vCP1452 immunogenicity in aged mice, whose CD4+ T cell function has been found impaired. This proposal is innovative in using molecular adjuvants to bypass CD4+ T cell help for the development of therapeutic HIV-1 vaccines for immunocompromised patients. The long-term goal of this study is to develop a novel therapeutic formulation of HIV-1 vaccines in combination with molecular adjuvants to induce more potent and long-lasting CTL and Ab responses in immunocompromised HIV-1-infected hosts. Plain language: This study will develop and evaluate a novel formulation of therapeutic HIV vaccine regimen in the absence of CD4+ T help in a mouse model, which roughly mimics an accelerated form of AIDS in humans. Data obtained from this study will provide key information for therapeutic vaccine development for young and aged people living with HIV/AIDS.