Circumventing antivector immunity: potential use of nonhuman adenoviral vectors

Abstract

Adenoviruses are efficient gene delivery vectors based on their ability to transduce a wide variety of cell types and drive high-level transient transgene expression. While there have been advances in modifying human adenoviral (HAdV) vectors to increase their safety profile, there are still pitfalls that need to be further addressed. Preexisting humoral and cellular immunity against common HAdV serotypes limits the efficacy of gene transfer and duration of transgene expression. As an alternative, nonhuman AdV (NHAdV) vectors can circumvent neutralizing antibodies against HAdVs in immunized mice and monkeys and in human sera, suggesting that NHAdV vectors could circumvent preexisting humoral immunity against HAdVs in a clinical setting. Consequently, there has been an increased interest in developing NHAdV vectors for gene delivery in humans. In this review, we outline the recent advances and limitations of HAdV vectors for gene therapy and describe examples of NHAdV vectors focusing on their immunogenicity, tropism, and potential as effective gene therapy vehicles.

FIG. 1.

Innate and adaptive antiadenoviral immune responses. (1) Activation of macrophages and natural killer (NK) cells by recognition of opsonized adenovirus (AdV) through antibody-constant fraction receptor (FcR). (2) Interleukin (IL)-1β maturation upon binding of arginine-glycine-aspartic acid (RGD) motif in the AdV penton base with macrophage β3 integrins. (3) Induction of IL-6 and IL-12 secretion in plasmacytoid dendritic cell (pDC) upon AdV DNA recognition through Toll-like receptor (TLR)-9. (4) Dendritic cell (DC) maturation through internalized immune complexes (ICs). (5) Triggering of T cell immune responses upon binding of AdV fiber shaft region to heparin-sensitive receptors on DCs. (6) Interferon (IFN)-α production by activated pDCs, conventional DCs (cDCs), and macrophage and IFN-α recognition by uninfected cells leading to a cellular antiviral state. (7) Induction of CXCL10 expression by AdV penton base RGD motif binding to α_v integrins. (8) Secretion of IFN-α and β by infected cells. (9) Classical complement pathway activation by virion neutralization with IgM or recognition by IgG. (10) Thrombocytopenia related to alternative complement pathway activation on AdVs. (11) Major histocompatibility complex class II (MHC-II) induction on professional antigen presenting cells (APCs) by IFN-γ signal promoting antigen presentation to helper T CD4+ cells. (12) Induction of B cell maturation and isotype switching through AdV antigen presentation by Th2-type T CD4+ cells. (13) Activation of T CD8+ cells through AdV antigen presentation by DC via MHC-I. (14) IL-2 production by Th1-type T CD4+ cells upon AdV antigen presentation by APCs through MHC-II, which activates T CD8+ cells. BCR, B cell receptor; C3b, complement component 3b; CAR, coxsackie virus and adenovirus receptor; IFN R, interferon receptor; TCR, T cell receptor.