Adenovirus vectors are also used for gene therapy. There are over 50 different human aden-ovirus serotypes, but current vectors are primarily derived from serotypes 2 and 5 (7). Most adenovirus vectors lack genes that are essential for virus replication, thus creating space for the insertion of a desired transgene (8). These viruses can only be grown in packaging cell lines that express the missing genes, allowing for complementation of the genetic defect.
Several qualities make adenoviruses good candidates for gene therapy. They can be produced and purified with high titers. Through the use of heterologous promoters and enhancers, they can effect high levels of transgene expression. Because the adenovirus DNA remains episomal, adenovirus vectors cannot effect insertional mutagenesis. Finally, adenovirus can infect and effect transgene expression in postmitotic nondividing cells.
Adenovirus vectors generally are not suitable for stable transgene expression. Because the virus does not integrate into the host cell's genome, it may not be retained by the daughter cells produced during cell replication. In addition, adenovirus vectors can induce antibody responses that can neutralize the ability of subsequent injections of adenovirus to infect cells in vivo. Moreover, the immune system can generate a cellular response to virus-infected cells, thereby clearing cells that express adenovirus-encoded proteins (9,10). However, this could be advantageous if the adenovirus infects tumor cells, potentially providing an adjuvant effect that could boost an otherwise weak response to tumor-associated antigens (11).
We found that adenovirus can infect CLL cells (12). The susceptibility to infection generally correlates with the relative expression of coxsackie adenovirus receptor (CAR) protein (13-15). CLL cells express low levels of CAR but can be infected by adenovirus at high multiplicity of infection (MOI). Uptake of virus appears to be mediated through interaction with integrins expressed on leukemia cells via a CAR-independent process that requires the virus to be present at a relatively high local concentration. Recognition of CAR expression is low in many human carcinomas, which has prompted development of adenovirus vectors capable of CAR-independent gene transfer (8,16,17). Such new developments may find their application in gene therapy strategies for CLL in vivo.
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