| Autor: |
Hemsath JR; Graduate Research Employee Program, Mayo Clinicgrid.66875.3a, Rochester, Minnesota, USA., Liaci AM; Interfaculty Institute of Biochemistry, University of Tübingengrid.10392.39, Tübingen, Germany.; Structural Biochemistry, Bijvoet Centre for Biomolecular Research, Utrecht University, Utrecht, The Netherlands., Rubin JD; Virology and Gene Therapy Graduate Program, Mayo Clinicgrid.66875.3a, Rochester, Minnesota, USA., Parrett BJ; Virology and Gene Therapy Graduate Program, Mayo Clinicgrid.66875.3a, Rochester, Minnesota, USA., Lu SC; Virology and Gene Therapy Graduate Program, Mayo Clinicgrid.66875.3a, Rochester, Minnesota, USA., Nguyen TV; Division of Infectious Diseases, Department of Medicine, Mayo Clinicgrid.66875.3a, Rochester, Minnesota, USA., Turner MA; Virology and Gene Therapy Graduate Program, Mayo Clinicgrid.66875.3a, Rochester, Minnesota, USA., Chen CY; Division of Infectious Diseases, Department of Medicine, Mayo Clinicgrid.66875.3a, Rochester, Minnesota, USA., Cupelli K; Interfaculty Institute of Biochemistry, University of Tübingengrid.10392.39, Tübingen, Germany., Reddy VS; Department of Integrative Structural and Molecular Biology, The Scripps Research Institute, La Jolla, California, USA., Stehle T; Interfaculty Institute of Biochemistry, University of Tübingengrid.10392.39, Tübingen, Germany., Liszewski MK; Division of Rheumatology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA., Atkinson JP; Division of Rheumatology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA., Barry MA; Division of Infectious Diseases, Department of Medicine, Mayo Clinicgrid.66875.3a, Rochester, Minnesota, USA.; Department of Immunology, Mayo Clinicgrid.66875.3a, Rochester, Minnesota, USA.; Department of Molecular Medicine, Mayo Clinicgrid.66875.3a, Rochester, Minnesota, USA. |
| Abstrakt: |
Human adenovirus serotype 26 (Ad26) is used as a gene-based vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and HIV-1. However, its primary receptor portfolio remains controversial, potentially including sialic acid, coxsackie and adenovirus receptor (CAR), integrins, and CD46. We and others have shown that Ad26 can use CD46, but these observations were questioned on the basis of the inability to cocrystallize Ad26 fiber with CD46. Recent work demonstrated that Ad26 binds CD46 with its hexon protein rather than its fiber. We examined the functional consequences of Ad26 for infection in vitro and in vivo. Ectopic expression of human CD46 on Chinese hamster ovary cells increased Ad26 infection significantly. Deletion of the complement control protein domain CCP1 or CCP2 or the serine-threonine-proline (STP) region of CD46 reduced infection. Comparing wild-type and sialic acid-deficient CHO cells, we show that the usage of CD46 is independent of its sialylation status. Ad26 transduction was increased in CD46 transgenic mice after intramuscular (i.m.) injection but not after intranasal (i.n.) administration. Ad26 transduction was 10-fold lower than Ad5 transduction after intratumoral (i.t.) injection of CD46-expressing tumors. Ad26 transduction of liver was 1,000-fold lower than that ofAd5 after intravenous (i.v.) injection. These data demonstrate the use of CD46 by Ad26 in certain situations but also show that the receptor has little consequence by other routes of administration. Finally, i.v. injection of high doses of Ad26 into CD46 mice induced release of liver enzymes into the bloodstream and reduced white blood cell counts but did not induce thrombocytopenia. This suggests that Ad26 virions do not induce direct clotting side effects seen during coronavirus disease 2019 (COVID-19) vaccination with this serotype of adenovirus. IMPORTANCE The human species D Ad26 is being investigated as a low-seroprevalence vector for oncolytic virotherapy and gene-based vaccination against HIV-1 and SARS-CoV-2. However, there is debate in the literature about its tropism and receptor utilization, which directly influence its efficiency for certain applications. This work was aimed at determining which receptor(s) this virus uses for infection and its role in virus biology, vaccine efficacy, and, importantly, vaccine safety. |
