Lentivirus Lentiviral vectors

To circumvent this problem, vectors that are based on lentiviruses have been developed. In contrast to prototypic retroviruses, lentiviruses do not require cell division for integration. Gene-therapy vectors have been developed from a broad spectrum of lentiviruses including human immunodeficiency vims (HIV), simian and feline immunodeficiency vims as well as visna/maedi vims. The most widely used lentiviral vector system is based on HIV-1. These vectors can efficiently transduce a broad spectrum of dividing and nondividing cells including neurons, hepatocytes, muscle cells, and hematopoietic stem cells [1,2]. 

A newer generation of retroviral vectors, based on the lentivirus, hold the same advantages of retroviral vectors with the added ability to transduce non-dividing cells efficiently. Pre-clinical studies with lentiviral vectors for the treatment of hemophilia have shown great promise. Using a feline immunodeficiency virus (FlV)-based vector, Stein et al. showed that 9 of 12 treated hemophilia A mice could express greater than 5 ng/ml factor VIII, six of which... 

The lentiviral vectors have safety concerns similar to the retroviral vector-based gene therapy products (1) the production of a replication competent lentivirus (RCL) during manufacturing and (2) the potential for insertional mutagenesis, resulting in oncogene activation. One concern unique to the lentiviral vectors is the possibility that the vector can be mobilized in vivo,... 

The use of vectors based on other primate lentiviruses (83,84) may also eliminate some of the concerns however, HIV-2 and simian immunodeficiency vims (SIV) are closely related to HI V-1. Therefore, vectors based on nonprimate lentiviruses like feline immunodeficiency virus (FIV), equine infectious anemia vims, and visna may be more acceptable (85-87). These viruses do not cause infection in humans due to restrictions in the envelope tropism. However, the risk associated with the introduction of nonhuman lentiviral vectors in human tissues is unknown, and the actual safety of these lentiviral vectors remains to be evaluated. 

Lentiviruses can infect non-dividing cells, thereby allowing stable gene transfer in post-mitotic mature neurons. Lentiviral vector-mediated delivery of short hairpin RNAs (shRNAs) results in persistent knockdown of gene expression. In addition, inducible lentiviral vectors offer a powerful tool for better assessing the function of a gene candidate in targeted neurons by an on-off system [1]. 

The envelope glycoproteins of wild-type retroviruses and lentiviruses bind to cell surface receptors to facilitate entry of the vims into the cytoplasm where the viral RNA is reverse transcribed to form a cDNA, the proviras. This provirus is translocated to the nucleus where it integrates into the host cell chromosomes and through the normal process of DNA transcription encodes new viral proteins and new viral RNA, which are assembled at the cell surface into new viral particles. Replication-defective retroviral and lentiviral vectors infect cells by similar mechanisms, but unlike wild-type viruses, the integrated provirus from these vectors encodes the therapeutic gene and viral particles are not produced. 

Similarly lentiviral vectors also integrate and are more likely to result in sustained gene expression (36,37). Moreover, levels of expression following airway administration of lentiviral vectors are low, and there is little information about the ethcacy of lentiviruses in injured lung (36,37). 

Esimone and coworkers, in their increasing study of West African lichen species, identified the utility of R. farinacea derivatives against lentiviruses and adenoviruses. Esimone et al. (2005) initially showed that the ethyl-acetate-soluble fraction ET4) from the lichen Ramalina farinacea inhibited the infectivity of lentiviral and adenoviral vectors, as well as wild-type HIV-1. Recorded antiviral activity was about 20 pg/ml. Preliminary mechanistic studies based on the addition of the extracts at different time points in the viral infection cycle (kinetic studies) led to the suggestion that early steps in the lentiviral or adenoviral replication cycle could be the major target of ET4. Inhibition of wild-type HIV-1 was also observed at a tenfold lower concentratiOTi of the extract. 

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