Potential for Mobilization

When viral vectors are used for the introduction of genes into the germline of animals, there exists a potential for inadvertent transmission of the gene to other individuals (not necessarily of the same species). This undesirable effect could occur if such an animal were to be infected with a virus sufficiently similar to the vector to package the vector into virions. For example, if a transgenic chicken were created using an avian retrovirus vector, then infection of the transgenic chicken with any related virus (such viruses are quite commonly found in commercial poultry operations) could lead to the production and release of a virus that could transmit the gene to other animals where its presence and expression might be highly undesirable, such as among wild bird populations. Generation of a replicating virus could occur in the absence of exogenous infection, since many species contain endogenous retroviruses in their genomes that could serve as agents of this kind of mobilization. For example, in cats carrying murine leukemia virus-based vector constructs, the introduced genes could be mobilized to other cats (or, at least theoretically, to their human hosts) by the endogenous feline leukemia viruses found in most animals. As discussed above, the use of vectors based on HIV has the potential to improve the efficiency of introduction of new genes into the germline of many animal species. Such germline vectors could, in principle, also be mobilized by HIV or a sufficiently close relative. Viruses closely related to HIV are found only in African primates; however, viruses of the same genus (Lentivirus) are fairly common in cats (feline immunodeficiency virus or FIV), cattle (bovine immunodeficiency virus or BIV), and sheep (visna-maedi virus or VMV; Rosenberg and Jolicouer, 1997). Despite the distant relationship, FIV has been shown to transfer HIV-based vector constructs from one cell to another, raising a serious concern that similar transfer of genes introduced by an HIV (or any lentivirus) vector could be mobilized among animals infected with these common viruses (Berkowitz et al., 2001; Browning et al., 2001).

A related concern arises with the use of mariner and related transposons (including sleeping beauty) to introduce germline DNA. Related elements have been found in large numbers (14 thousand copies) in the human genome (Lander et al., 2001) and planaria, nematodes, centipedes, mites, insects (Robertson, 1997), and humans (Robertson and Zumpano, 1997), suggesting the possibility of horizontal gene flow via transposition among highly diverse hosts (Robertson and Lampe, 1995; Hartl et al., 1997; Hamada et al., 1997; Kordis and Gubensek, 1998; 1999; Jordan et al., 1999; Sundararajan et al., 1999). These potentially could be mobilized by the constructs used to transfer mariner-like elements into the germline, and their insertion into genes could give rise to unexpected genetic damage. Horizontal gene transfer also might be mediated by ingestion of DNA (Houck et al., 1991; Yoshiyama et al., 2001).



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