Development of Molecular Adjuvants for Therapeutic HIV-1 Vaccines

描述(由申请人提供)：针对HIV-1的抗逆转录病毒治疗，即所谓的高效抗逆转录病毒疗法(HAART)的使用所取得的进展，今天受到终身给药的成本和毒性的限制。已经提出了一种创新的治疗策略，以增强感染艾滋病毒-1疫苗的患者的免疫系统，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接种疫苗后仍有能力引发免疫反应。HIV-1感染的患者通常表现出免疫防御功能受损，这是由于CD4T细胞的丧失导致的，CD4T细胞是建立细胞介导和抗体(Ab)介导的免疫反应的关键。为了克服目前免疫治疗性HIV-1疫苗开发的这一挑战，我们建议开发一种异种PRIME-BOOST疫苗方法，在免疫的初始和增强阶段都添加CD40配体，CD40配体是肿瘤坏死因子超家族(TNFSF)的成员，以增强免疫低下的宿主的抗病毒反应。最近在小鼠系统中的研究表明，通过与树突状细胞(DC)的相互作用，抗病毒CD8细胞毒性T淋巴细胞(CTL)反应需要CD4T细胞的帮助。此外，CD40L与树突状细胞上的CD40连接可以替代或绕过CD4T细胞的帮助。因此，我们推测，将CD40L作为分子佐剂与疫苗联合使用可能是一种新的策略，可以在HIV-1感染等CD4T细胞缺陷状态下诱导有效的抗病毒CTL和抗病毒抗体反应。我们有两个具体目标：1)确定在疫苗接种的初始和加强阶段都添加CD40L作为分子佐剂的异源DNA Prime-ALVAC Boost疫苗方法，是否可以在没有CD4 T细胞帮助的情况下改善vCP1452(一种目前获得许可的ALVAC-HIV疫苗)免疫的HIV-1特异性CTL和Ab应答；2)确定在疫苗接种的初始和加强阶段都添加CD40L作为分子佐剂的DNA Prime-ALVAC Boost策略是否也能改善老年小鼠的HIV疫苗vCP1452的免疫原性，因为已发现老年小鼠的CD4 T细胞功能受损。这一建议在使用分子佐剂绕过CD4T细胞方面具有创新性，有助于为免疫功能低下的患者开发治疗性HIV-1疫苗。这项研究的长期目标是开发一种新的HIV-1疫苗与分子佐剂相结合的治疗性配方，以在免疫受损的HIV-1感染宿主中诱导更有效和更持久的CTL和Ab反应。简而言之：这项研究将在小鼠模型中开发和评估一种新的治疗性艾滋病毒疫苗方案，在没有CD4T帮助的情况下，该模型大致模拟人类艾滋病的一种加速形式。从这项研究中获得的数据将为青年和老年艾滋病毒/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.