Development of Molecular Adjuvants for Therapeutic HIV-1 Vaccines

描述（由申请人提供）：使用抗逆转录病毒治疗（称为高效抗逆转录病毒治疗（HAART））对抗HIV-1的进展今天受到终身给药药物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HIV-1疫苗感染患者的免疫系统，并帮助限制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疫苗接种后仍然有能力引发免疫应答。患有HIV-1感染的患者通常表现出由CD 4 + T细胞的损失引起的免疫防御受损，所述CD 4 + T细胞对于启动细胞介导的和抗体（Ab）介导的免疫应答两者都是必需的。为了克服目前免疫缺陷HIV-1疫苗开发的这一挑战，我们建议开发一种异源引发-加强疫苗方法，在疫苗接种的引发和加强阶段添加CD 40配体（共刺激分子的肿瘤坏死因子超家族（TNFSF）的成员），以增加免疫功能低下的宿主中缺乏CD 4 + T细胞帮助的抗病毒反应。最近对小鼠系统的研究表明，通过与树突状细胞（DC）的相互作用，抗病毒CD 8+细胞毒性T淋巴细胞（CTL）反应需要CD 4 + T细胞的帮助。此外，来自CD 4 + T细胞的帮助可以通过将DC上的CD 40 L与CD 40连接来替代或绕过。因此，我们假设，采用CD 40 L作为分子佐剂与疫苗组合可能代表一种新的策略，以诱导有效的抗病毒CTL和抗体反应的CD 4 + T细胞缺陷的国家，如HIV-1感染。我们有两个具体目标：1）确定在疫苗接种的初免和加强阶段添加CD 40 L作为分子佐剂的异源DNA初免-ALVAC加强疫苗方法是否可以改善对vCP 1452的HIV-1特异性CTL和Ab应答（一种目前许可的ALVAC-HIV疫苗）免疫，在缺乏CD 4 + T细胞辅助的情况下，在CD 4 + T细胞耗尽的鼠模型中; 2）确定在疫苗接种的初免和加强阶段添加CD 40 L作为分子佐剂的DNA初免-ALVAC加强策略是否也可以改善HIV疫苗vCP 1452在已发现其CD 4 + T细胞功能受损的老年小鼠中的免疫原性。该提案在使用分子佐剂绕过CD 4 + T细胞帮助开发用于免疫功能低下患者的治疗性HIV-1疫苗方面具有创新性。本研究的长期目标是开发一种新的HIV-1疫苗与分子佐剂组合的治疗制剂，以在免疫功能低下的HIV-1感染宿主中诱导更有效和持久的CTL和Ab应答。简单的语言：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，该模型在没有CD 4 + T辅助的情况下，大致模拟了人类艾滋病的加速形式。从这项研究中获得的数据将为年轻人和老年人艾滋病毒/艾滋病患者的治疗性疫苗开发提供关键信息。

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.