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Adenovirus (Ad) vaccine vectors have found widespread use as vaccine platforms against multiple infections and cancers, and multiple serotypes have been shown to differ significantly in their biological properties and immune phenotypes. Our laboratory and others have previously described differential innate immune stimulation elicited by various Ad serotypes. Here, we show that Ad serotype 5 (Ad5) traffics rapidly to the nucleus following infection, whereas Ad35 and Ad26 accumulate in late endosomes 2 to 8 h postinfection. Innate immune cytokine elicitation by all Ad serotypes was abrogated by blockade of endosomal acidification, cathepsin B, and caspase 1, suggesting that virus interactions with acid-dependent sensors, such as Toll-like receptor- and cathepsin-dependent inflammasome activation in late endosomes, may trigger innate immunity. These data suggest a mechanism by which Ad vectors from various serotypes differentially trigger innate antiviral pathways via distinct intracellular trafficking to late endosomes. [ABSTRACT FROM AUTHOR]

Adenovirus (Ad) vaccine vectors have proven highly immunogenic in multiple experimental models, but the innate immune responses induced by these vectors remain poorly characterized. Here we report innate cytokine responses to 5 different Ad vectors in 26 rhesus monkeys. Vaccination with adenovirus serotype 35 (Ad35), Ad26, and Ad48 induced substantially higher levels of antiviral (gamma interferon [IFN-], 10-kDa gamma interferon-induced protein [IP-10]) and proinflammatory (interleukin 1 receptor antagonist [IL-1RA], IL-6) cytokines than vaccination with Ad5 on day 1 following immunization. In vitro studies with capsid chimeric vectors and receptor-blocking monoclonal antibodies suggested that fiber-receptor interactions, as well as other capsid components, were critical for triggering these innate responses. Moreover, multiple cell populations, including dendritic cells, monocytes/macrophages, and T lymphocytes, contributed to these innate cytokine profiles. These data demonstrate that Ad35, Ad26, and Ad48, which utilize CD46 as their primary cellular receptor, induce significantly greater innate cytokine responses than Ad5, which uses the coxsackievirus and adenovirus receptor (CAR). These differences in innate triggering result in markedly different immunologic milieus for the subsequent generation of adaptive immune responses by these vaccine vectors. [ABSTRACT FROM AUTHOR]

Adenovirus vectors are widely used as vaccine candidates for a variety of pathogens, including HIV-1. To date, human and chimpanzee adenoviruses have been explored in detail as vaccine vectors. The phylogeny of human and chimpanzee adenoviruses is overlapping, and preexisting humoral and cellular immunity to both are exhibited in human populations worldwide. More distantly related adenoviruses may therefore offer advantages as vaccine vectors. Here we describe the primary isolation and vectorization of three novel adenoviruses from rhesus monkeys. The seroprevalence of these novel rhesus monkey adenovirus vectors was extremely low in sub-Saharan Africa human populations, and these vectors proved to have immunogenicity comparable to that of human and chimpanzee adenovirus vaccine vectors in mice. These rhesus monkey adenoviruses phylogenetically clustered with the poorly described adenovirus species G and robustly stimulated innate immune responses. These novel adenoviruses represent a new class of candidate vaccine vectors. Although there have been substantial efforts in the development of vaccine vectors from human and chimpanzee adenoviruses, far less is known about rhesus monkey adenoviruses. In this report, we describe the isolation and vectorization of three novel rhesus monkey adenoviruses. These vectors exhibit virologic and immunologic characteristics that make them attractive as potential candidate vaccine vectors for both HIV-1 and other pathogens. [ABSTRACT FROM AUTHOR]

The cellular receptor utilized by adenovirus serotype 26 (Ad26) has remained unclear. Here we show that Ad26 transduction is CD46-dependent and is efficiently blocked by anti-CD46 but not anti-CAR antibodies, demonstrating that Ad26 utilizes CD46 as a primary cellular receptor. Moreover, following Ad26 vaccination of rhesus monkeys, we did not observe sustained activation of peripheral or mucosal vector-specific CD4+ T lymphocytes. These data contribute to our understanding of Ad26 as a candidate vaccine vector. [ABSTRACT FROM AUTHOR]