Adenovirus vector induced innate immune responses: impact upon efficacy and toxicity in gene therapy and vaccine applications

Abstract

Extensively characterized, modified, and employed for a variety of purposes, adenovirus (Ad) vectors are generally regarded as having great potential by many applied virologists who wish to manipulate and use viral biology to achieve beneficial clinical outcomes. Despite widespread functional prominence and utility (i.e., Ad-based clinical trials have begun to progress to critical Phase III levels, it has recently become apparent that investigations regarding the innate immune response to Ads may reveal not only reasons behind previous failures, but also reveal novel insights that will allow for safer, more efficacious uses of this important gene transfer platform. Insights gained by the exploration of Ad induced innate immune responses will likely be most important to the fields of vaccine development, since Ad-based vaccines are regarded as one of the more promising vaccine platforms in development today. Adenovirus is currently known to interact with several different extracellular, intracellular, and membrane-bound innate immune sensing systems. Past and recent studies involving manipulation of the Ad infectious cycle as well as use of different mutants have shed light on some of the initiation mechanisms underlying Ad induced immune responses. More recent studies using microarray-based analyses, genetically modified cell lines and/or mouse mutants, and advanced generation Ad vectors have revealed important new insights into the scope and mechanism of this cellular defensive response. This review is an attempt to synthesize these studies, update Ad biologists to the current knowledge surrounding these increasingly important issues, as well as highlight areas where future research should be directed. It should also serve as a sobering reality to researchers exploring the use of any gene transfer vector, as to the complexities potentially involved when contemplating use of such vectors for human applications.

Figure 1. Intracellular and membrane bound sensors of Adenovirus

Toll-Like Receptors (TLRs) are membrane bound Pattern Recognition Receptors (PRRs) that recognize conserved molecular structures known as pathogen-associated molecular patterns (PAMPs) found on invading pathogens. (A) Based on the cell type, Ad has been shown to elicit innate immune responses through TLR9 and MyD88 dependent pathways. Ad induced stimulation of these pathways results in rapid activation of over 30 transcription factors including NF-κB, and IRF3, as well as release of numerous cytokines and chemokines. (B) Ablation of either MyD88 or TLR9 does not fully suppress these innate responses, suggesting redundant systems, such as other TLR proteins, or adaptors such as TRIF, exist that stimulate immune response pathways that are independent of MyD88 and/or TLR9. (C) Intracellular sensors of dsDNA, such as RIG-I, are also likely PRRs involved in Ad induced innate signaling in various cell types resulting in similar activation of downstream pathways including activation of IRF3 and release of Type I IFNs. The effector molecules, downstream of the activated receptors, are currently unknown, but are likely shared with pathways known to be activated by other PAMPs. NFκB, nuclear factor kappa B; TRIF, TIR domain-containing adaptor protein inducing interferon beta; MyD88, myeloid differentiation primary response gene-88; IRF, interferon response factor; IFN, interferon; IL, interleukin; MCP, monocyte chemoattractant protein; RANTES, regulated on activation, normal T-cell expressed and secreted; MIP, macrophage inflammatory protein; IP, interferon gamma inducible protein; MAVS , mitochondrial antiviral signaling.