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.

Uncleaved prefusion-optimized (UFO) design can stabilize diverse HIV-1 envelope glycoproteins (Envs). Single-component, self-assembling protein nanoparticles (1c-SApNP) can display 8 or 20 native-like Env trimers as vaccine candidates. We characterize the biophysical, structural, and antigenic properties of 1c-SApNPs that present the BG505 UFO trimer with wildtype and modified glycans. For 1c-SApNPs, glycan trimming improves recognition of the CD4 binding site without affecting broadly neutralizing antibodies (bNAbs) to major glycan epitopes. In mice, rabbits, and nonhuman primates, glycan trimming increases the frequency of vaccine responders (FVR) and steers antibody responses away from immunodominant glycan holes and glycan patches. The mechanism of vaccine-induced immunity is examined in mice. Compared with the UFO trimer, the multilayered E2p and I3-01v9 1c-SApNPs show 420 times longer retention in lymph node follicles, 20-32 times greater presentation on follicular dendritic cell dendrites, and up-to-4 times stronger germinal center reactions. These findings can inform future HIV-1 vaccine development.

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Purpose Oncolytic viruses are self-amplifying anti-cancer agents that make use of the natural ability of viruses to kill cells. Adenovirus serotype 5 (Ad5) has been extensively tested against solid cancers, but less so against B cell cancers since these cells do not generally express the coxsackie and adenoviral receptor (CAR). To determine if other adenoviruses might have better potency, we “mined” the adenovirus virome of 55 serotypes for viruses that could kill B cell cancers. Experimental Design 15 adenoviruses selected to represent Ad species B, C, D, E, and F were tested in vitro against cell lines and primary patient B cell cancers for their ability to infect, replicate in, and kill these cells. Select viruses were also tested against B cell cancer xenografts in immunodeficient mice. Results Species D adenoviruses mediated most robust killing against a range of B cell cancer cell lines, against primary patient marginal zone lymphoma cells, and against primary patient CD138+ myeloma cells in vitro. When injected into xenografts in vivo, single treatment with select species D viruses Ad26 and Ad45 delayed lymphoma growth. Conclusions Relatively unstudied species D adenoviruses have a unique ability to infect and replicate in B cell cancers as compared to other adenovirus species. These data suggest these viruses have unique biology in B cells and support translation of novel species D adenoviruses as oncolytics against B cell cancers.

Although there are 55 serotypes of adenovirus that infect humans, Ad5 is the most widely studied due to the availability of commercial kits for its genetic manipulation. In fact, engineered adenovirus serotype 5 is currently being used in all of the 87 global clinical trials utilizing adenovirus for the treatment of cancer. Unfortunately, Ad5 is one of the most seroprevalent serotypes, meaning that this virus has to confront additional immunological barriers to be effective in Ad5-immune patients. In this work, we compare Ad5 to 13 other adenoviral serotypes from species B, C, D, and E for oncolytic potential in both immunodeficient mouse and immunocompetent hamster models. Our results indicate that species D adenoviruses are not effective oncolytics against most solid tumors. Conversely, lower seroprevalence Ad6 and Ad11 hade anti-cancer activity comparable to Ad5. This work strongly supports the consideration of Ad6-based oncolytic therapies for the treatment of breast, ovarian, kidney, and liver tumors.