Preintegration Complex

A nuclear receptor that is a key transcription factor in adipocytes. It plays a critical role in the control of adipocyte differentiation and is involved in the regulation of the expression of specific adipokines, including leptin and adiponectin. It has anti-inflammatory actions and is the target of the thiazolidinedione drugs. The preintegration complex is a complex of retroviral DNA and proteins that translocates from the cytosol into the nucleus prior to integration. Gene Therapy... 

Famet CM, Wang B, Lipford JR, Bushman FD. Differential inhibition of HIV-1 preintegration complexes and purified integrase protein by small molecules. Proc Natl Acad Sci USA 1996 93 9742-9747. 

Bukrinsky, M.I., Sharova, N., Dempsey, M.P., Stanwick, T.L., Bukrinsky, A.G., Haggerty, S. et al. (1992) Active nuclear import of human immunodeficiency vims type 1 preintegration complexes. Proc. Natl. Acad. Sci. USA, 89, 6580-6584. 

Popov, S., Rexach, M., Ratner, L., Blobel, G. and Bukrinsky, M. (1998a) Viral protein R regulates docking of the HIV-1 preintegration complex to the nuclear pore complex. J. Biol. Chem., 273, 13347-13352. 

The viral protein R (Vpr) of HIV-1 plays a significant role early in the viral life cycle by facilitating the nuclear import of the preintegration complex in non-dividing cells. The C-terminal domain of Vpr (Vpr52-96), which condenses plasmid DNA, mediates DNA transfection in a variety of human and non-human cell lines (Table 16.7). The Vpr52-96 sequence... 

The aromatic polycyclic diones hypericin and pseudohypericin, which are present in plants of the family Hypericum (St. John s wort), have been accredited with anti-HIV activity for more than a decade. They possess the capacity to inactivate HIV virions directly as well as to interfere with their assembly or processing. Hypericin has received continued interest as a potential therapeutic agent and was more recently found to interact with preintegration complexes (PICs) and thus affect the proviral DNA integration process (De Clercq, 2000). 

Reverse transcription and nuclear translocation of the preintegration complex are thought to be limiting steps in retroviral transduction, especially in terminally differentiated postmitotic cells. Proviral DNA synthesis of all retroviruses depends strongly on cellular conditions, and low nucleoside pools or absence of cellular cofactors may explain the incomplete reverse transcription in quiescent or stationary cells (56, 65-70). 

A major limitation in the use of oncoietroviral vectors is their inability to transduce nondividing cells. Oncoretroviruses are unable to transport their preintegration complex containing the proviral DNA across the nuclear membrane in the absence of cell division. During mitosis, the nuclear membrane breaks down and only then is the large preintegration complex able to enter the nucleus (73,74). 

Lentiviral vectors on the other hand are able to transduce nondividing cells. The HIV-1 preintegration complex has karyophilic properties due to the presence of nuclear localization signals (NLS) in the viral proteins matrix and integrase. These unique features allow the preintegration complex to cross the nuclear membrane using the cellular nuclear import machinery in the absence of mitosis (75-78). 

FV, however, is unable to replicate in nondividing cells despite efficient nuclear localization of the preintegration complex due to a NLS in gag (79,80). Nevertheless, efficient transduction of postmitotic cells has been demonstrated using FV vectors in which transgene expression is driven by an internal CMV promotor (81), indicating that vims replication in nondividing cells is probably blocked at the transcriptional level. 

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