Adenoviruses: History
Please note this is an old version of this entry, which may differ significantly from the current revision.
Subjects: Virology
Contributor:

Adenoviruses represent exceptional candidates for wide-ranging therapeutic applications, from vectors for gene therapy to oncolytics for cancer treatments. The first ever commercial gene therapy medicine was based on a recombinant adenovirus vector, while most recently, adenoviral vectors have proven critical as vaccine platforms in effectively controlling the global coronavirus pandemic.

  • adenovirus
  • endocytosis
  • vectors
  • gene therapy

1. Introduction

Adenoviruses (AdVs) can cause mild health problems, like acute respiratory, gastrointestinal, and ocular infections, but have no oncogenic potential in humans [1]. To ensure viral progeny, AdVs need to efficiently infect permissive cells that will enable both adenoviral entry and replication of DNA. The life cycle of AdVs can be simply divided into several stages: binding to a receptor expressed on a cell surface, entry into the cell by endocytosis, endosomal escape, trafficking through the cytoplasm, and docking at the nuclear pore complex (NPC), followed by nuclear entry of the adenoviral genome. Once adenoviral DNA enters the nucleus, expression of early and late genes allows assembly of new viral particles and their release from the host cell is enabled.
Thanks to their features, like the relative ease with which their genome can be modified as well as relative tolerance towards genetic manipulation, AdVs have been recognized as promising vectors for gene transfer. Today, according to the Wiley database on Gene Therapy Trials Worldwide, AdVs present 17.5% of vectors used in gene therapy clinical trials (https://a873679.fmphost.com/fmi/webd/GTCT; accessed on 10 August 2021). The first ever commercial gene therapy medicine was recombinant adenovirus encoding human p53 tumor suppressor gene, Gendicine, registered for the treatment of head and neck cancers on the market in China [2]. Besides being vectors for gene transfer, AdVs are widely used as vectors for vaccination. Numerous AdV vaccine candidates for treating infectious diseases and cancer are under investigation, with the most important milestone being achieved when European Medicines Agency recently approved three AdV-vector-based vaccines: one against Ebola (Zabdeno; Ad26.ZEBOV [3]) and two against Covid-19 (ChAdOx1 nCoV-19 [4] and Ad26.COV2.S [5]), demonstrating the efficacy of AdV-based vaccines as tools for controlling pandemic outbreaks.

We distinguish the two types of commonly used adenoviral vectors: replication-defective and oncolytic adenoviruses. Due to molecular engineering, replication-defective AdVs cannot replicate in infected cells, however they provide high expression of transgenes with minimum expression of AdV proteins. Unlike replication-defective AdVs (also known as vectors), oncolytic AdVs selectively replicate in and lyse cancer cells, and are, therefore, commonly used vectors in clinical trials for cancer gene therapy [6]. The world first oncolytic virus product was also an adenovirus, Oncorine (H101), an oncolytic adenovirus intended to be used in combination with chemotherapy as a treatment for patients with late-stage refractory nasopharyngeal cancer [7]. Currently, a large number of AdV platforms are being developed for oncology applications, for example, Enadenotucirev, a clinical stage oncolytic AdV with broad potential to target solid tumor carcinomas [8]; DNX-2401; Delta-24-RGD oncolytic AdV, developed as immunotherapeutic treatment for recurrent malignant glioma [9]; and TILT-123, a human AdV5/AdV3 chimeric oncolytic adenovirus encoding for tumor necrosis factor alpha and human interleukin 2 aimed at generating an anti-cancer immune response [10].

To fulfil its role as a vector, an AdV needs to successfully deliver its DNA genome to the host nucleus, a process highly influenced by AdV intracellular translocation. In this review, we discuss which factors are involved in AdV endocytosis, focusing mainly on receptors and endocytic scaffold proteins, as well as the influence of a particular type of endocytosis on AdV intracellular trafficking.

Human adenoviruses (HAdVs) are non-enveloped double stranded DNA viruses with icosahedral capsids of approximately 90 nm in diameter and mass of ~150 megadaltons [11]. HAdVs consist of 13 structural proteins that form the outer capsid of icosahedral geometry and the inner core, where double-stranded DNA is bound with the core proteins. Major building blocks of the HAdV capsid are hexon and penton. There are 240 copies of the hexon trimer, and 12 pentons comprising an extended fiber protein non-covalently attached to the penton base protein. The fiber protein is composed of tail, shaft, and knob domains, the latter containing several loops. In addition, capsids comprise minor proteins IIIa, VI, VIII, and IX [12]. HAdVs are classified into seven subgroups, A–G [13], according to hemagglutination and serum neutralization reactions or by genome sequencing and bioinformatics analysis (International Committee on Taxonomy of Viruses—ICTV). HAdV infection starts with binding to the primary receptor at the cell surface. Primary receptor usage differs between different HAdVs serotypes. After initial attaching to the primary receptor, HAdV binds αv integrins on the cell surface through an RGD peptide sequence present in the penton base of the virus [14]. This interaction triggers internalization of HAdV, as well as a number of signaling events that lead to virus cell entry within the endosomal compartment [15]. Partial disassembly of the capsid occurs prior to membrane penetration, however the escape of incoming adenoviruses from endosomes is dependent on the viral membrane lytic protein VI, whose lytic activity is pH-independent [16][17]. Once liberated from the endosome, the fibreless HAdV capsid is transported towards the nucleus along a network of microtubules [18] and motor proteins, such as dynein (unidirectional movement) or kinesin (bidirectional) [19][20]. Final docking of the HAdV capsid occurs at the nuclear pore and the HAdV genome enters the nucleus [21], where it remains episomal. A scheme of HAdV cell entry is presented on Figure 1.
Pharmaceutics 13 01585 g001

This entry is adapted from the peer-reviewed paper 10.3390/pharmaceutics13101585

References

  1. Ghebremedhin, B. Human adenovirus: Viral pathogen with increasing importance. Eur. J. Microbiol. Immunol. 2014, 4, 26–33.
  2. Peng, Z. Current status of gendicine in China: Recombinant human Ad-p53 agent for treatment of cancers. Hum. Gene Ther. 2005, 16, 1016–1027.
  3. Pollard, A.J.; Launay, O.; Lelievre, J.D.; Lacabaratz, C.; Grande, S.; Goldstein, N.; Robinson, C.; Gaddah, A.; Bockstal, V.; Wiedemann, A.; et al. Safety and immunogenicity of a two-dose heterologous Ad26.ZEBOV and MVA-BN-Filo Ebola vaccine regimen in adults in Europe (EBOVAC2): A randomised, observer-blind, participant-blind, placebo-controlled, phase 2 trial. Lancet Infect. Dis. 2021, 21, 493–506.
  4. Voysey, M.; Clemens, S.A.C.; Madhi, S.A.; Weckx, L.Y.; Folegatti, P.M.; Aley, P.K.; Angus, B.; Baillie, V.L.; Barnabas, S.L.; Bhorat, Q.E.; et al. Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: An interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK. Lancet 2021, 397, 99–111.
  5. Sadoff, J.; Gray, G. Safety and Efficacy of Single-Dose Ad26.COV2.S Vaccine against Covid-19. N. Engl. J. Med. 2021, 384, 2187–2201.
  6. Cunliffe, T.G.; Bates, E.A.; Parker, A.L. Hitting the Target but Missing the Point: Recent Progress towards Adenovirus-Based Precision Virotherapies. Cancers 2020, 12, 3327.
  7. Liang, M. Oncorine, the World First Oncolytic Virus Medicine and its Update in China. Curr. Cancer Drug Targets 2018, 18, 171–176.
  8. Illingworth, S.; Di, Y.; Bauzon, M.; Lei, J.; Duffy, M.R.; Alvis, S.; Champion, B.; Lieber, A.; Hermiston, T.; Seymour, L.W.; et al. Preclinical Safety Studies of Enadenotucirev, a Chimeric Group B Human-Specific Oncolytic Adenovirus. Mol. Ther. Oncolytics 2017, 5, 62–74.
  9. Lang, F.F.; Conrad, C.; Gomez-Manzano, C.; Yung, W.K.A.; Sawaya, R.; Weinberg, J.S.; Prabhu, S.S.; Rao, G.; Fuller, G.N.; Aldape, K.D.; et al. Phase I Study of DNX-2401 (Delta-24-RGD) Oncolytic Adenovirus: Replication and Immunotherapeutic Effects in Recurrent Malignant Glioma. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2018, 36, 1419–1427.
  10. Havunen, R.; Siurala, M.; Sorsa, S.; Grönberg-Vähä-Koskela, S.; Behr, M.; Tähtinen, S.; Santos, J.M.; Karell, P.; Rusanen, J.; Nettelbeck, D.M.; et al. Oncolytic Adenoviruses Armed with Tumor Necrosis Factor Alpha and Interleukin-2 Enable Successful Adoptive Cell Therapy. Mol. Ther. Oncolytics 2017, 4, 77–86.
  11. Mangel, W.F.; San Martín, C. Structure, function and dynamics in adenovirus maturation. Viruses 2014, 6, 4536–4570.
  12. Nemerow, G.R.; Stewart, P.L.; Reddy, V.S. Structure of human adenovirus. Curr. Opin. Virol. 2012, 2, 115–121.
  13. Lefkowitz, E.J.; Dempsey, D.M.; Hendrickson, R.C.; Orton, R.J.; Siddell, S.G.; Smith, D.B. Virus taxonomy: The database of the International Committee on Taxonomy of Viruses (ICTV). Nucleic Acids Res. 2018, 46, D708–D717.
  14. Stewart, P.L.; Nemerow, G.R. Cell integrins: Commonly used receptors for diverse viral pathogens. Trends Microbiol. 2007, 15, 500–507.
  15. Greber, U.F.; Willetts, M.; Webster, P.; Helenius, A. Stepwise dismantling of adenovirus 2 during entry into cells. Cell 1993, 75, 477–486.
  16. Wiethoff, C.M.; Wodrich, H.; Gerace, L.; Nemerow, G.R. Adenovirus protein VI mediates membrane disruption following capsid disassembly. J. Virol. 2005, 79, 1992–2000.
  17. Suomalainen, M.; Luisoni, S.; Boucke, K.; Bianchi, S.; Engel, D.A.; Greber, U.F. A direct and versatile assay measuring membrane penetration of adenovirus in single cells. J. Virol. 2013, 87, 12367–12379.
  18. Suomalainen, M.; Nakano, M.Y.; Keller, S.; Boucke, K.; Stidwill, R.P.; Greber, U.F. Microtubule-dependent plus- and minus end-directed motilities are competing processes for nuclear targeting of adenovirus. J. Cell Biol. 1999, 144, 657–672.
  19. Scherer, J.; Vallee, R.B. Adenovirus recruits dynein by an evolutionary novel mechanism involving direct binding to pH-primed hexon. Viruses 2011, 3, 1417–1431.
  20. Zhou, J.; Scherer, J. Role of kinesins in directed adenovirus transport and cytoplasmic exploration. PLoS Pathog. 2018, 14, e1007055.
  21. Strunze, S.; Engelke, M.F.; Wang, I.H.; Puntener, D.; Boucke, K.; Schleich, S.; Way, M.; Schoenenberger, P.; Burckhardt, C.J.; Greber, U.F. Kinesin-1-mediated capsid disassembly and disruption of the nuclear pore complex promote virus infection. Cell Host Microbe 2011, 10, 210–223.
  22. Hendrickx, R.; Stichling, N.; Koelen, J.; Kuryk, L.; Lipiec, A.; Greber, U.F. Innate immunity to adenovirus. Hum. Gene Ther. 2014, 25, 265–284.
  23. Iacobelli-Martinez, M.; Nemerow, G.R. Preferential activation of Toll-like receptor nine by CD46-utilizing adenoviruses. J. Virol. 2007, 81, 1305–1312.
  24. Barlan, A.U.; Griffin, T.M.; McGuire, K.A.; Wiethoff, C.M. Adenovirus membrane penetration activates the NLRP3 inflammasome. J. Virol. 2011, 85, 146–155.
  25. Barlan, A.U.; Danthi, P.; Wiethoff, C.M. Lysosomal localization and mechanism of membrane penetration influence nonenveloped virus activation of the NLRP3 inflammasome. Virology 2011, 412, 306–314.
  26. Lee, J.S.; Mukherjee, S.; Lee, J.Y.; Saha, A.; Chodosh, J.; Painter, D.F.; Rajaiya, J. Entry of Epidemic Keratoconjunctivitis-Associated Human Adenovirus Type 37 in Human Corneal Epithelial Cells. Invest. Ophthalmol. Vis. Sci. 2020, 61, 50.
  27. Yousuf, M.A.; Zhou, X.; Mukherjee, S.; Chintakuntlawar, A.V.; Lee, J.Y.; Ramke, M.; Chodosh, J.; Rajaiya, J. Caveolin-1 associated adenovirus entry into human corneal cells. PLoS ONE 2013, 8, e77462.
  28. Lee, J.S.; Ismail, A.M.; Lee, J.Y.; Zhou, X.; Materne, E.C.; Chodosh, J.; Rajaiya, J. Impact of dynamin 2 on adenovirus nuclear entry. Virology 2019, 529, 43–56.
  29. Custers, J.; Kim, D.; Leyssen, M.; Gurwith, M.; Tomaka, F.; Robertson, J.; Heijnen, E.; Condit, R.; Shukarev, G.; Heerwegh, D.; et al. Vaccines based on replication incompetent Ad26 viral vectors: Standardized template with key considerations for a risk/benefit assessment. Vaccine 2021, 39, 3081–3101.
  30. Zahn, R.; Gillisen, G.; Roos, A.; Koning, M.; van der Helm, E.; Spek, D.; Weijtens, M.; Grazia Pau, M.; Radošević, K.; Weverling, G.J.; et al. Ad35 and ad26 vaccine vectors induce potent and cross-reactive antibody and T-cell responses to multiple filovirus species. PLoS ONE 2012, 7, e44115.
  31. Iacobelli-Martinez, M.; Nepomuceno, R.R.; Connolly, J.; Nemerow, G.R. CD46-utilizing adenoviruses inhibit C/EBPbeta-dependent expression of proinflammatory cytokines. J. Virol. 2005, 79, 11259–11268.
  32. Teigler, J.E.; Kagan, J.C.; Barouch, D.H. Late endosomal trafficking of alternative serotype adenovirus vaccine vectors augments antiviral innate immunity. J. Virol. 2014, 88, 10354–10363.
  33. Greber, U.F.; Webster, P.; Weber, J.; Helenius, A. The role of the adenovirus protease on virus entry into cells. EMBO J. 1996, 15, 1766–1777.
  34. Smith, J.S.; Xu, Z.; Tian, J.; Palmer, D.J.; Ng, P.; Byrnes, A.P. The role of endosomal escape and mitogen-activated protein kinases in adenoviral activation of the innate immune response. PLoS ONE 2011, 6, e26755.
  35. Zaiss, A.K.; Vilaysane, A.; Cotter, M.J.; Clark, S.A.; Meijndert, H.C.; Colarusso, P.; Yates, R.M.; Petrilli, V.; Tschopp, J.; Muruve, D.A. Antiviral Antibodies Target Adenovirus to Phagolysosomes and Amplify the Innate Immune Response. J. Immunol. 2009, 182, 7058.
More
This entry is offline, you can click here to edit this entry!
Video Production Service