The study investigates the prevalence and diversity of Adeno-associated viruses (AAVs) in human tissues, highlighting their potential as gene therapy vectors. AAV infections are prevalent in humans, with liver and bone marrow being the most common sites. Molecular techniques detected endogenous AAV sequences in 18% of human tissues screened. Sequence analysis revealed a diverse array of molecular forms, including clades that share functional and serologic similarities. One prominent clade is a hybrid of two previously described AAV serotypes, while another clade is found in both humans and nonhuman primates, suggesting cross-species transmission. The study also explored the biological tropisms and functional properties of different AAV clones and clades, providing insights into their potential use in gene therapy. The findings suggest that natural AAV infections are common and that the virus may transmit via the gastrointestinal tract and viremia. The presence of latent AAVs and their ability to recombine and cross species barriers raise concerns about the emergence of new infectious agents and the potential complications of AAV gene therapy.The study investigates the prevalence and diversity of Adeno-associated viruses (AAVs) in human tissues, highlighting their potential as gene therapy vectors. AAV infections are prevalent in humans, with liver and bone marrow being the most common sites. Molecular techniques detected endogenous AAV sequences in 18% of human tissues screened. Sequence analysis revealed a diverse array of molecular forms, including clades that share functional and serologic similarities. One prominent clade is a hybrid of two previously described AAV serotypes, while another clade is found in both humans and nonhuman primates, suggesting cross-species transmission. The study also explored the biological tropisms and functional properties of different AAV clones and clades, providing insights into their potential use in gene therapy. The findings suggest that natural AAV infections are common and that the virus may transmit via the gastrointestinal tract and viremia. The presence of latent AAVs and their ability to recombine and cross species barriers raise concerns about the emergence of new infectious agents and the potential complications of AAV gene therapy.