More than 80 different adenovirus types can cause infections in humans, occurring in the respiratory or gastrointestinal tracts, or the eyes. Adenoviruses generally cause acute infections but can persist despite antibody and cell-based immune responses. However, immunosuppressed individuals and some pediatric patients are at risk of mortality. In addition to humans and other mammals, the Adenoviridae family can infect birds, reptiles, amphibians, and fish.
The adenovirus was discovered in the mid-1950s during the long-term cultivation of tonsil and adenoid tissues, leading to an early description as adenoid degeneration viruses. Two further research groups isolated the virus from patients with acute pharyngitis and conjunctivitis, and also in infected army recruits (Rowe et al. 1953, Huebner et al. 1954, Hilleman and Werner 1954). Later some adenoviruses were found to have oncogenic potential (Huebner et al. 1962). Adenovirus research also provided key insights into molecular mechanisms. Among them, RNA splicing (Berk and Sharp 1978), the description of a molecular folding chaperone (AdV-C2/5 100K) needed for the folding of the adenovirus hexon protein (Cepko and Sharp 1982), and the discovery that the adenovirus early transcription unit 3/K19 (E3/K19) inhibits the transport of major histocompatibility (MHC) HLA class I (HLA-I) to the host cell surface (Burgert and Kvist 1985). In the 1990s adenovirus-based gene transfer saw some success in the treatment of cystic fibrosis by the transfer of fibrosis transmembrane conductance regulator (CFTR) cDNA (Zabner et al. 1993). The adenovirus was selected for gene therapy because of its genetic stability and high gene transduction efficiency, ultimately though, longterm success was blocked by the strong innate and adaptive immune responses it induces. However, this characteristic makes it a good vaccine vector.
In the last two decades, work has continued to harness the adenovirus for gene and cancer therapies (Watanabe et al. 2021, Thambi et al. 2022), and vaccines. Its most recent application was in the generation of the Oxford/AstraZeneca (ChAdOx1-S) COVID-19 vaccine to protect against SARS-CoV-2 infection. For more information check out Bio-Rad’s resource page on COVID-19 or view our SARS-CoV-2 antibody range.
The term memory inflation was coined in the lab of Paul Klenerman during research on the importance of CD8+ T cells in viral diseases, which are key to controlling intracellular infections. Klenerman was specifically seeking to elucidate the background to the high numbers of virus-specific CD8+ T cells that remain functional long after the initial infection has passed. Using a murine cytomegalovirus (CMV) model, the research found that the initial CD8+ T cell population increase and decrease associated with viral infections was followed by a sustained increase of certain epitope-specific CD8+ T cells. The key being that only selected viral epitopes drove this expansion, termed memory inflation. Strikingly, after one year, 20% of CD8+ T cells were specific for one epitope (Karrer et al. 2003). A recombinant adenoviral vector model (Bolinger et al. 2013) extended this work showing that the inflationary memory epitope reactive cells retained an effector memory surface phenotype (CD62Llow, CD127−, IL-15Rβ−) and were unable to produce IL-2, typical of effector memory CD8+ T cells. In contrast, conventional epitopes were detected by classic central memory phenotype cells, that is, expressing CD62L, cytokine receptors for IL-7 and IL-15, and producing low levels of IL-2. Over time, the phenotype of inflationary memory CD8+ T cells was confirmed as low expression levels for CCR7, CD62L, CD28, CD27, and CD127, and high for CX3CR1 and KLRG1.
The importance of the adenovirus model lies in being able to further the understanding of CD8+ T cell memory inflation while also advancing its potential as a vaccine vector. Adenovirus-based vaccine work is far ahead of other viral models. While human adenovirus-based vaccines are effective in generating an immune response to cancer and viral targets, they suffer from decreased efficacy due to the presence of long-term immunity against adenovirus in many subjects (Priddy et al. 2008, Snook et al. 2019). However, a way around this is to use chimeric chimpanzee adenovirus vectors which have shown success as a vaccine against the hepatitis C virus and more recently SARS-CoV2 (Barnes et al. 2012, Folegatti et al. 2020, Ewer et al. 2021). The complete picture of how this effective immunity is induced is not ready yet, but further details have been discovered.
While several projects have helped to define the phenotype of inflationary memory CD8+ T cells as high expression for CX3CR1 and KLRG1 and low expression for CCR7, CD62L, CD28, CD27, and CD127; work by Bolinger et al. helped to provide more detail on conditions needed for induction of immunity. A replication-defective, adenovirus vector succeeded in long-lasting transduction of peripheral organs with β-galactosidase that carried two epitopes—one generating a central memory CD8+ T cell pool and the other driving an inflating effector memory T cell response. While the latter did not require antigen processing in professional antigen-presenting cells, it did require MHC II-expressing cells (Bolinger et al. 2013). New research supplies more data on possible cell types for maintaining inflating memory CD8+ T cells. An in vitro human and a mouse model, both using adenovirus vector vaccination, point toward fibroblastic stromal cells as the candidate cell type. In the mouse model, the vector targeted lung tissue leading to a remodeling of the fibroblastic stromal cell anatomy that was then able to maintain immune cell clusters. The reprogramming of the fibroblastic stromal cells also generated an IL-33 producing subset. IL-33 can stimulate several T cell types and contribute to cytokine networks in pathogen removal and tissue repair.
While significant and lifesaving progress has been made using adenovirus-based vectors for immunizations, more work is necessary to define the immunological landscape and fully elucidate the factors needed for the generation and maintenance of inflationary memory CD8+ T cells.
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