Modulating the immune response to adenovirus vectors through NF-kB/IRF3 activatio

描述（由申请人提供）：尽管疫苗在限制传染病传播方面取得了巨大成功，但针对主要人类病原体（如HIV）的疫苗开发仍存在大量未满足的需求。在此背景下，表达靶抗原的复制缺陷型5型腺病毒载体（AdV）疫苗由于其相对安全性和诱导体液和细胞介导的应答的能力而受到相当大的关注。宿主对感染因子或疫苗的应答需要高度保守的先天免疫诱导模式识别受体（PRR），包括Toll样受体（TLR）和RIG-I样受体。尽管存在多种PRR，但认为只有少数细胞内途径对PRR诱导宿主应答至关重要。其中关键的是属于NF-κ B和IRF家族的转录因子。因此，这些转录因子在促进免疫应答中充当细胞内佐剂。本文提出的研究的主要目标是确定是否可以通过表达关键的细胞内佐剂来增强AdV的疫苗潜力。为此，本文提出的研究将系统地评估激活NF-kB和IRF通路的不同关键分子的佐剂潜力和作用机制。如果成功，我们的研究将对未来设计AdV和潜在的非AdV疫苗产生重大影响。提出了两个具体目标。目的1：表达不同细胞内佐剂的AdV的产生、体外和体内表征。目的2：确定1型干扰素在细胞内清除剂诱导的AdV免疫应答增强中的作用。

DESCRIPTION (provided by applicant): Despite the tremendous success of vaccines in limiting the spread of infectious diseases, there remains a large unmet need for development of vaccines against major human pathogens such as HIV. Within this context, replication-deficient type 5 adenovirus vector (AdV) vaccines expressing target antigens have received considerable attention because of their relative safety and ability to induce humoral and cell-mediated responses. Host responses against infectious agents or vaccines require highly conserved innate immunity-inducing pattern recognition receptors (PRR), including Toll-like Receptors (TLRs) and RIG-I-like receptors. Despite the presence of multiple PRR, only a few intracellular pathways are thought to be critically important for induction of host responses by PRR. Key amongst them are transcription factors belonging to the NF-kB and IRF families. These transcription factors therefore serve as intracellular adjuvants in promoting immune responses. The main goal of studies proposed here is to determine whether the vaccine potential of AdV can be enhanced through expression of key intracellular adjuvants. To this end, the studies proposed here will systematically evaluate the adjuvant potential and mechanism of action of different key molecules that activate NF-kB and IRF pathways. If successful, our studies can have a major impact on the future design of AdV and potentially non-AdV vaccines for both infectious diseases and cancer. Two specific aims are proposed. Aim 1: Generation, in vitro and in vivo characterization of AdV expressing distinct intracellular adjuvants. Aim 2: Defining the role of type 1 IFN in intracellular adjuvant-induced enhancement of AdV immune responses.