NIAID Clinical Trial Planning Grant

描述(申请人提供)：尽管有效的联合抗逆转录病毒疗法(CART)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，但我们现在必须专注于解决CART的局限性。HIV-1感染的联合疗法没有有效地克服与病毒持久性有关的问题，这些问题可能有助于提高免疫激活水平。慢性免疫激活可能会限制免疫重建，并易发生慢性感染的非免疫性并发症。我们建议调查一种基于免疫的辅助疗法是否可以解决这些局限性。具体地说，我们假设，用灭活的自体病毒冲击的自体树突状细胞(DC)体外免疫，并用强有力的佐剂Poly-ICLC(多肌苷-多胞酸-多L-赖氨酸羧甲基纤维素；Hiltonol(R)，Oncovir)免疫，将刺激先天和获得性免疫反应，这反过来将减少残留的病毒负担，减少免疫激活，并在抑制车中断时增强病毒学控制。通过DC疫苗接种，我们希望绕过HIV在体内使用的一些损害内源性DC功能的机制，从而损害T细胞反应的有效形成。此外，给予一种有效的全身佐剂Poly-ICLC(Hiltonol(R)，Oncovir)，应该可以通过诱导成熟来增强疫苗的免疫原性，从而提高内源性DC的免疫原性，从而允许注射的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，纠正HIV感染患者DC功能缺陷对于诱导足够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。 与公共卫生相关：目前对HIV+受试者进行终身抗病毒治疗的治疗模式，患者依从性近乎完美，以避免出现抗药性艾滋病毒，这与显著的毒性、未能完全消除病毒以及对一般健康的实质性损害有关。通过以树突状细胞为基础的疫苗接种促进病毒特异性免疫，目的是刺激先天和获得性免疫反应，从而减少残留病毒负担，减少免疫激活，并加强病毒学控制，从而成功阻断CART。

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.