Retroviruses defective

Mueller, G. M., McKenzie, L. R., Homanics, G. E., Watkins, S. C., Robbins, P. D. and Paul, H. S. Complementation of defective leucine decarboxylation in fibroblasts from a maple syrup urine disease patient by retrovirus-mediated gene transfer. Gene Ther. 2 461-468,1995. 

Gene therapy offers another potential avenue to fix the defective gene. The therapy itself is by no means straightforward. In a French gene therapy trial, three boys with SCID were treated using retrovirus-based gene therapy. They later developed cancer and one died of leukemia. Reviews showed that the retrovirus inserted near oncogenes and promoted development of cancer. 

Retrotransposons lack an env gene and so cannot form viral particles. They can be thought of as defective viruses, trapped in cells. Comparisons between retroviruses and eukaryotic transposons suggest that reverse transcriptase is an ancient enzyme that predates the evolution of multicellular organisms. 

There are two classes of retrotrotransposons those with long terminal repeats (LTRs) and those without (LTRs). The first group is closely related to retroviruses, but its members lack genes for envelope proteins. They do carry gag and pol genes similar to those of retroviruses (Fig. 28-3). Most retrotransposons are defective and do not move. Over evolutionary time they accumulate in the genome, sometimes to the extent that the genome size grows enormously. This... 

Mann R, Muhigan RC, Baltimore D. 1983. Construction of a retrovirus packaging mutant and its use to produce helper-free defective retrovirus. Cell. 33 153-159. 

The initial viral-based gene delivery experiments were performed in vitro using replication defective retroviral vectors in an attempt to transduce endothelial cells (Yao et al., 1991). Preliminary viral-based in vivo cardiovascular gene delivery experiments were also performed using retroviral vectors and demonstrated this vector system s ability to successfully transduce vascular endothelial cells (Newman et al., 1991). Although attempts at direct transduction of the carotid artery were not successful, it was established that efficient endothelial transduction could be achieved through the retrovirus-mediated infection of cells ex vivo and their subsequent arterial seeding in vivo (Lynch et al., 1992). 

There are also immunodeficiency states that are primary and can be caused by phagocytic cell defects, deficiencies in the complement system, B- and T-cell deficiency, and other causes. Secondary immunodeficiency disorders can result from malnutrition, cytotoxic drugs, infections with pyrogenic bacteria, and infections with an RNA retrovirus, as in the acquired immunodeficiency syndrome (AIDS). 

Major concerns in the use of retroviral vectors are the possibility of vector mobilization and recombination with defective (endogenous) retroviruses in the target cell. This led to the development of self-inactivating vectors (SIN) (38). In these vectors, the viral promotor and enhancer regions in the 3 U3 are deleted, thus preventing LTR-driven transcription in the transduced cells. Furthermore, transgene expression in these vectors is exclusively driven by an internal promotor, which improves the use of regulatory and tissue-specific promoters. 

It may also be noted, as per an Encyclopedia Britannica article, subsequently to be cited, that retroviruses are often defective and require the assistance of other, nondefective helper retroviruses. (In retroviruses, which are commonly associated with cancer, the RNA provides the cellular instructions rather than the DNA.) Usually, these helper viruses are involved in transforming fibroblastic cells, as in connective tissue, and the result is malignant sarcomas. Otherwise, without assistance, the defective retroviruses will act to transform blood cell precursors, and the end result is leukemia. 

Unlike infection by other retroviruses, HIV Infection eventually kills host cells, causing the defects In the Immune response characteristic of AIDS. 

The first clue that cells could be transformed by defects in normal genes came from studies of the composite retroviruses. Although this class of animal retroviruses have not been linked to human cancer, cell-culture studies demonstrated that the retroviral genome encoded all the information required for cell transformation. 

Guidotti, J., Akli, S., Castelnau-Ptakhine, L., Kahn, A., and Poenaru, L., Retrovirus-mediated enzymatic correction of Tay-Sachs defect in transduced and non-transduced cells. Hum Mol Genet 7 (1998) 831-838. 

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