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posted 24. November 2004 10:15
PLoS Biology, November 23, 2004
From a PLoS Synopsis
Retroviral Gene Vectors Show Clear Target Preferences
Copyright: © 2004 Public Library of Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Citation: (2004) Retroviral Gene Vectors Show Clear Target Preferences. PLoS Biol 2(12): e443.
Lentiviruses—which include AIDS and SIV (simian immunodeficiency virus)—can infect nondividing cells simply by slipping through nuclear pores. Oncoretroviruses—such as murine leukemia virus, or MLV, the vector type used for the vast majority of previous clinical trials, including the trial complicated by leukemia in two patients—must wait until the nuclear membrane dissolves during cell division. Once integrated into the host genome, the provirus—and its therapeutic gene—will persist through each new cell division—a trait that underlies its usefulness as a vector as well as its risk. Retroviruses that insert near proto-oncogenes can activate these genes and set the cell on the path to tumorigenesis. Until recently, researchers assumed this risk was extremely low because retroviral integration was thought to be random—an assumption recently undercut by a number of studies that mapped retroviral integration in different cell lines.
Of nearly 1,000 integration sites identified, 760 could be mapped to unique corresponding sites in the human genome (432 MLV and 328 SIV). While both MLV and SIV vectors tended to integrate within genes, MLV showed a strong preference for the starting end of genes, most likely to result in gene activation. In contrast, SIV showed a preference for genomic regions of high gene density, but not for specific sites within a gene. Surprisingly, MLV targeted one gene—known previously to be involved in spontaneous leukemias and in murine retroviral oncogenesis—seven times, a “highly nonrandom” result suggesting that such insertions may occur far more often than previously thought. About 40 genes, including seven known oncogenes, were targeted more than once by one or both vectors. Such differences, Dunbar and colleagues note, “likely reflect the vectors' distinct mechanisms for accessing DNA and integrating,” which could in turn affect their risk of causing insertional mutagenesis. Even though the vectors tend to integrate nonrandomly and can target oncogenes, however, none of the monkeys showed signs of ill effects such as leukemia.
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[ 03. December 2004, 20:34: Message edited by: ISCID News Editor ]