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ADENOVIRUS YECTORAND METHODOLOGYTO MANI_J ULATETHEADENOVIRUS GENOME5 The invention relates to an isolated adenovims, and/ora variant adenovirus;optionally said adenovirus is modified to include a heterologous nucleic acidmolecule; pharmaceutical compositions comprising said adenovirus; and methods toconstruct and manipulate any recombinant adenovirus genome.10 Adenoviruses (Ads) were first isolated in 1953 by Rowe et a1. (Rowe et a1., 1953)who were trying to establish cell-lines from adenoidal tissue of children removedduring tonsillectomy and from military recruits with febrile illness. Adenoviruses arewidespread in nature, infecting birds, mammals and man. Belonging to the familyAdenoviTidae and the genus Mastadenovirus, over 50 human adenovirus serotypes15 have been classified within6 subgenera (A-F), according to their hemaggultinationpattern, their DNA homology and other criteria (Shenk, 2001). The most prevalentserotypes are those of subgenusC (1, 2,5 and 6). Together with some serotypes ofsubgenusB andE these viruses area frequent cause of acute upper respiratory tract(URT) infections, i.e. "colds", and other respiratory pathologies. They have been20 shownto cause some5% of acute respiratory diseases in children under5 years of ageand 10% of the pneumonias (Horwitz, 2001). In addition, Ads also causea numberofother types of infection often associated withtheeye (e.g conjunctivitis and epidemickeratoconjunctivitis), the gastrointestinal tract (e.g. gastroenteritis) or the urogenitaltract (e.g cystitis). The organ tropism is distinct for different human adenovirus25 subgenera. Often these diseases are self-limiting, unless the immune system issuppressed, such as in transplantation patients (Horwitz, 2001). Ads have also beenused therapeutically for vaccination and for gene therapy (Horwitz, 2001; Russell,2000).Gene therapy aims at treating both genetic (e.g. cancer, haemophilia) and infectious30 diseases (e.g. AIDS) by introducing new genetic material into selected cells. Themajor challenge is to deliver the gene safely and efficiently into the desired targetcells. Among the biggest physical hurdles that gene delivery technologies have toovercome arethe various lipid membranes ofthe cell, e.g. the plasma membrane orthe nuclear membrane. The plasma membrane is impermeable to charged