NIAID Clinical Trial Planning Grant

尽管有效的联合抗逆转录病毒疗法（cART）已经大大降低了与人类免疫缺陷病毒（HIV-1）感染相关的发病率和死亡率，但我们现在必须关注解决cART的局限性。HIV-1感染的联合治疗尚未有效克服与病毒持久性相关的问题，这可能导致免疫激活水平的提高。慢性免疫激活可能限制免疫重建和易患慢性感染的非免疫性并发症。我们建议研究一种辅助免疫疗法是否可以解决这些局限性。具体来说，我们假设用体外灭活的自体病毒脉冲的自体树突状细胞（DC）免疫，并给予强效佐剂Poly-ICLC（多肌苷-多胞酸-聚l -赖氨酸羧甲基纤维素；Hiltonol(r), Oncovir），将刺激先天和适应性免疫反应，从而减少残留的病毒负担，降低免疫激活，并在抑制性cART中断时加强病毒学控制。通过DC疫苗接种，我们希望绕过HIV在体内使用的一些机制，从而损害内源性DC功能，从而损害T细胞反应的有效形成。此外，注射强效全身佐剂Poly-ICLC （Hiltonol(r), Oncovir）应该通过诱导成熟来增强疫苗的免疫原性，从而增强内源性DC的免疫原性，从而允许注射DC相关抗原的有效交叉呈递。成功的DC免疫将提供有价值的概念证明，即纠正艾滋病毒感染患者DC功能缺陷对于诱导充分的免疫反应至关重要，为研究更实用的基于免疫的DC靶向疗法铺平道路，这些疗法可能适用于更广泛的患者群体。

DESCRIPTION (provided by applicant): Abstract Though effective combination antiretroviral therapy (cART) has drastically reduced the morbidity and mortality associated with human immunodeficiency virus (HIV-1) infection, we must now focus on addressing the limitations of cART. Combination therapy for HIV-1 infection has not effectively overcome issues relating to viral persistence, which likely contribute to increased levels of immune activation. Chronic immune activation may limit immune reconstitution and predispose to non-immunologic complications of chronic infection. We propose to investigate whether an adjunctive immune based therapy can address these limitations. Specifically, we hypothesize that immunization with autologous dendritic cells (DC) pulsed with inactivated autologous virus ex vivo and administered with a potent adjuvant, Poly-ICLC, (polyinosinic-polycytidylic acid-poly-L-lysine carboxymethylcellulose; Hiltonol(r), Oncovir), will stimulate innate and adaptive immune responses which will in turn reduce residual viral burden, decrease immune activation, and enhance virologic control when suppressive cART is interrupted. Through DC vaccination, we expect to bypass some of the mechanisms that HIV employs in vivo to compromise endogenous DC function and thus, impair effective formation of T cell responses. Furthermore, administration of a potent systemic adjuvant, Poly-ICLC (Hiltonol(r), Oncovir), should enhance vaccine immunogenicity by inducing the maturation, and consequently the immunogenicity of endogenous DC, allowing for efficient cross-presentation of injected DC-associated antigens. Successful DC immunization would provide valuable proof-of-concept that correction of defects in DC function in HIV-infected patients is vital to induction of adequate immune responses, paving the way for investigations of more practical immune based, DC-targeted therapies that may be applicable to a broader patient population. PUBLIC HEALTH RELEVANCE: The current treatment paradigm of lifelong antiviral therapy for HIV+ subjects with near perfect patient adherence to avoid the emergence of drug resistant HIV is associated with significant toxicity, failure to completely eliminate virus and substantial compromise of general health. By promoting virus-specific immunity through dendritic cell-based vaccination the goal is to stimulate innate and adaptive immune responses which will in turn reduce residual viral burden, decrease immune activation, and enhance virologic control so that cART can be successfully interrupted.