TAILIEUCHUNG - An Introduction to Molecular Medicine and Gene Therapy - part 8

Sản xuất trong tế bào của một protein CD4 hòa tan (sCD4) có thể ngăn chặn cả các ràng buộc của các hạt truyền nhiễm HIV và sản xuất của các hạt virus mới từ một tế bào bị nhiễm bão hòa tất cả các protein vỏ có sẵn. Đính kèm một tín hiệu duy trì lưới nội chất | TRANSDOMINANT NEGATIVE PROTEINS 273 FIGURE Cellular protein-based approaches for the inhibition of HIV-1 replication. The intracellular production of a soluble CD4 protein sCD4 can prevent both the binding of infectious HIV particles and the production of new virus particles from an infected cells by saturating all of the available envelope protein. The attachment of a endoplasmic reticulum ER retention signal KDEL to the CD4 protein brings about the inhibition of virus replication by retaining the gp160 envelope complexes with the endoplasmic reticulum. The incorporation of a lysosomal targeting sequence into the CD4 protein leads to the inhibition of gp160 expression through targeted degradation in the lysosomes. The expression of singlechain antibodies intrabodies can also lead to the retention of viral proteins in the ER by specific interaction with the BiP protein. by inducing or repressing cellular factors that in turn influence viral gene expression. One of the most successful in vitro uses of endogenous cellular proteins to inhibit an infectious agent is the use of a soluble version of the HIV receptor CD4 sCD4 . The T helper cell antigen CD4 functions as the receptor for the HIV through the physical interaction of the HIV envelope glycoprotein gp120 and the CD4 protein. Based on these results investigators have demonstrated that sCD4 protein can effectively bind to and inhibit HIV infection in CD4 cells. The effect of this strategy is to compete for binding of HIV to cellular CD4 with high concentrations of sCD4. In order for this strategy to be efficacious a high level of continuous expression of sCD4 will be required. Retroviral vectors expressing sCD4 have been shown to protect T-cell lines from HIV infection in vitro. A significant limitation to this strategy is the ability to achieve sufficiently high levels of sCD4 to neutralize HIV effectively. The use of sCD4 for the gene therapy of HIV infection in a clinical setting has been disappointing. .

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