Advances and future challenges in adenoviral vector pharmacology and targeting

Abstract

Adenovirus is a robust vector for therapeutic applications, but its use is limited by our understanding of its complex in vivo pharmacology. In this review we describe the necessity of identifying its natural, widespread, and multifaceted interactions with the host since this information will be crucial for efficiently redirecting virus into target cells. In the rational design of vectors, the notion of overcoming a sequence of viral "sinks" must be combined with re-targeting to target populations with capsid as well as shielding the vectors from pre-existing or toxic immune responses. It must also be noted that most known adenoviral pharmacology is deduced from the most commonly used serotypes, Ad5 and Ad2. However, these serotypes may not represent all adenoviruses, and may not even represent the most useful vectors for all purposes. Chimeras between Ad serotypes may become useful in engineering vectors that can selectively evade substantial viral traps, such as Kupffer cells, while retaining the robust qualities of Ad5. Similarly, vectorizing other Ad serotypes may become useful in avoiding immunity against Ad5 altogether. Taken together, this research on basic adenovirus biology will be necessary in developing vectors that interact more strategically with the host for the most optimal therapeutic effect.

Fig. (1)

Schematic of Ad capsid structure. (a) Cryo-electron micrograph reconstruction of the Ad5 capsid. The dotted triangle overlays one of the 20 facets of the icosahedron. (b) Diagram of the adenoviral capsid showing a "group of nine" hexon trimers, penton bases, and fiber n-terminus that is observed in cryo-EM. (c) Addition of flexible fiber structures to B that are not observed in cryo-EM.

Fig. (2)

Phylogenetic Tree of Human Adenoviruses. Full genome comparison of 34 completed Ad sequences groups viruses with species grouping according to genetic similarity.

Fig. (3)

Adenovirus delivery upon systemic injection. (a) Distribution of virion delivery including largest pharmacologic “sinks”. 1 = Liver, 2 = Spleen, 3 = Kidney, 4 = Lung, 5 = Bloodstream. Schematic of viral migration from the blood stream into the parenchyma of liver: (b) within the lobule structures of the liver and (c,d) within one lobule. (c) represents flow of virus from the triad to the central vein looking down into the sinusoid. (d) represents permeation of virus from inside the sinusoid out into the parenchyma via fenestrations. (d) also shows other pharmacologic paths virions may take including outflow in the the lymph and bile.