Lentiviruses

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]. 

Kennedy JM, Hoke A et al (2004) Peripheral neuropathy in lentivirus infection evidence of inflammation and axonal injury. AIDS 18(9) 1241-1250 Keswani SC, Pardo CA et al (2002) HIV-associated sensory neuropathies. AIDS 16(16) 2105-2117... 

Zhu Y, Jones G et al (2005) Lentivirus infection causes neuroinflammation and neuronal injury in dorsal root ganglia pathogenic effects of STAT-1 and inducible nitric oxide synthase. J Immunol 175(2) 1118-1126... 

The cultured hippocampal neurons infected with a control lentivirus or one expressing a short hairpin RNA against CPEB3 (siCPEB3- 4) for... 

AIDS was initially described in the U.S. in 1981, although sporadic cases probably occurred for at least two decades prior to this. By 1983, the causative agent, now termed HIV, was identified. HIV is a member of the lentivirus subfamily of retroviruses. It is a spherical, enveloped particle, 100-150 nm in diameter, and contains RNA as its genetic material (Figure 13.13). 

African coast, such as Senegal and the Ivory Coast. HIV-2 also causes AIDS, although there are some indications that it is less able to do so than HIV-1. It is interesting that the virus that is most closely related to HIV-2 is not HIV-1, but a lentivirus found in sooty mangabey monkeys (simian immunodeficiency virus or SIVSM). SIVSM does not cause disease in sooty mangabeys. 

One of the most commonly used vectors, these viruses naturally insert their RNA, in the form of reverse-transcribed DNA, into the chromosomes of dividing cells. Most retroviruses can traverse the nuclear membranes of dividing cells only an exception is the lentivirus (of which HIV is an example). 

A lentivirus-based system to functionally silence genes in primary mammalian cells, stem cells and transgenic mice by RNA interference. Nat Genet 33 401-406... 

Retroviruses require proliferative target cells to mediate effective gene transfer. Lentiviruses, the class of retrovirus that includes human immunodeficiency virus, are an exception. They can also integrate in nondividing cells. An additional obstacle for retroviruses is the high susceptibility of the virus particle to humoral factors that ablate their gene transfer capacity. Perhaps most important, retroviruses, even when used ex vivo, pose a low but real risk of cancer. 

Features Retrovirus Lentivirus Adenovirus Adeno- Associated Virus Plasmid... 

There is a wide variety of vectors used to deliver DNA or oligonucleotides into mammalian cells, either in vitro or in vivo. The most common vector systems are based on viral [retroviruses (9, 10), adeno-associated virus (AAV) (11), adenovirus (12, 13), herpes simplex virus (HSV) (14)] andnonviral [cationic liposomes (15,16), polymers and receptor-mediated polylysine-DNA] complexes (17). Other viral vectors that are currently under development are based on lentiviruses (18), human cytomegalovirus (CMV) (19), Epstein-Barr virus (EBV) (20), poxviruses (21), negative-strand RNA viruses (influenza virus), alphaviruses and herpesvirus saimiri (22). Also a hybrid adenoviral/retroviral vector has successfully been used for in vivo gene transduction (23). A simplified schematic representation of basic human gene therapy methods is described in Figure 13.1. 

GFP gene under control of CMV to retinal cells by injection into the subretinal space of eyes in rats the GFP gene was efficiently expressed in both photoreceptor cells and retinal pigment epithelium predominant expression in photoreceptor cells was achieved using the rhodopsin promoter. The transduction efficiency was high and photoreceptor cells in >80% of the area of whole retina were expressing GFP (76). Intron-containing constructs have been successfully introduced into recent versions of lentivirus vectors (77). 

Recently, a series of lentivirus vectors were developed for transduction of hepa-tocytes in vivo (78). Various promoters, such as the human CMV, the human phos-phoglycerate kinase (PGK) and the mouse albumin promoter, were introduced into the FlIV-1-based vector. These vectors showed enhanced nuclear translocation in hepatocytes and improved transgene expression. Interestingly, targeted expression to the liver could be accomplished by the use of the albumin promoter. Therapeutic levels of human factor IX were achieved after a single injection. 

Kafri, T. (2001). Lentivirus vectors difficulties and hopes before clinical trials. Cum Opin. Mol. Then, 3, 316-326. 

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