HIV-1-Derived Lentiviral Vectors
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The primary vectors of choice for gene therapy applications have been oncoretroviruses due to their simple genetic organization and their ability to integrate into the host cell genome without incurring cellular toxicity (ANDERSON 1998). However, these vectors require cell division for integration to occur (MILLER et al. 1990) due to a requirement for nuclear envelope breakdown to allow entry of the viral integration complex into the nucleus (ROE et al. 1993). This presents a major obstacle for in vivo or ex vivo transduction of non-dividing cells such as neurons, hepatocytes, muscle fibres, quiescent lymphocytes, and haematopoietic stem cells, as these cells are either inaccessible by such vectors, or must be manipulated in potentially detrimental ways to facilitate cell division and vector integration. For this reason, interest in recent years has turned to lentiviruses, due to their ability to infect and integrate in certain types of non-dividing cells (WEINBERG et al. 1991; BUKRINSKY et al. 1993; LEWIS and EMERMAN 1994). One lentivirus on which much work has been focused to derive vectors for gene therapy has been HIV-1, as it is the best characterized of the lentiviruses. The remainder of this review will focus on the properties of HIV-1 that allow it to efficiently infect non-dividing cells, and on the development of progressively safer and more efficient HIV-1-derived vectors over the past few years.
KeywordsNuclear Import Transfer Vector Nondividing Cell Human Immunode Woodchuck Hepatitis Virus
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- Anderson WF (1998) Human Gene Ther Nature 392:25–30Google Scholar
- Bukovsky A, Dull T, Follenzi A, Nguyen M, Kelly M, McGuinness R, Malech H, Naldini L (2000) Novel design of HIV-based vector system with no viral sequences overlap between packaging and transfer vector constructs. Mol Ther 1:S139Google Scholar
- Bukrinsky MI, Haffar OK (1999) HIV-1 nuclear import: in search of a leader. Front Biosci 4:772–781Google Scholar
- Chameau P, Mirambeau G, Roux P, Paulous S, Buc H, Clavel F (1994) HIV-1 reverse transcription. A termination step at the center of the genome. J Mol Biol 241:651–662Google Scholar
- Coffin J, Hughes SH, Varmus HE (2000) Retroviruses. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY.Google Scholar
- Consiglio A, Quattrini A, Martino S, Bensadoun JC, Dolcetta D, Trojani A, Benaglia G, Marchesini S, Cestari V, Oliverio A, Bordignon C, Naldini L (2001) In vivo gene therapy of metachromatic leukodystrophy in lentiviral vectors: correlation of neuropathology and protection against learning impairments in affected mice. Nat Med 7:310–316PubMedGoogle Scholar
- Hill CM, Deng H, Unutmaz D, KewalRamani VN, Bastiani L, Gorny MK, Zolla-Pazner S, Littman DR (1997) Envelope glycoproteins from human immunodeficiency virus types 1 and 2 and simian immunodeficiency virus can use human CCR5 as a coreceptor for viral entry and make direct CD4-dependent interactions with this chemokine receptor. J Virol 71:6296–6304PubMedGoogle Scholar
- Kordower JH, Emborg ME, Bloch J, Ma SY, Chu Y, Leventhal L, McBride J, Chen E-Y, Palfi S, Roitberg BZ, Brown WD, Holden JE, Pyzalski R, Taylor MD, Carvey P, Ling Z, Trono D, Hantraye P, Deglon N, Aebischer P (2000) Neurodegeneration prevented by lentiviral vector delivery of GDNF in primate models of Parkinson’s disease. Science 290:767–773PubMedGoogle Scholar
- Mangasarian A, Trono D (1997b) The multifaceted role of HIV Nef. Res Virol pp 30–33Google Scholar
- Schubert U, Anton LC, Bacik I, Cox JH, Bour S, Bennink JR, Orlowski M, Strebel K, Yewdell JW (1998) CD4 glycoprotein degradation induced by human immunodeficiency virus type 1 Vpu protein requires the function of proteasomes and the ubiquitin-conjugating pathway. J Virol 72:2280–2288PubMedGoogle Scholar
- von Schwedler UK, Stemmler TL, Klishko VY, Li S, Albertine KH, Davis DR, Sundquist WI (1998) Proteolytic refolding of the HIV-1 capsid protein amino-terminus facilitates viral core assembly. EMBO J 17:1555–1568Google Scholar