This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mhashilkar, A. M. Articles by Marasco, W. A. Search for Related Content PubMed PubMed Citation Articles by Mhashilkar, A. M. Articles by Marasco, W. A.

 Previous Article  |  Next Article 

J. Virol., 09 1997, 6486-6494, Vol 71, No. 9
Copyright © 1997, American Society for Microbiology

Inhibition of human immunodeficiency virus type 1 replication in vitro by a novel combination of anti-Tat single-chain intrabodies and NF- kappa B antagonists

AM Mhashilkar, DK Biswas, J LaVecchio, AB Pardee and WA Marasco
Division of Human Retrovirology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.

Human immunodeficiency virus type 1 (HIV-1) Tat, an early regulatory protein that is critical for viral gene expression and replication, transactivates the HIV-1 long terminal repeat (LTR) via its binding to the transactivation response element (TAR) and, along with other cellular factors, increases viral transcription initiation and elongation. Tat also superactivates the HIV-1 promoter through a TAR- independent mechanism, including tumor necrosis factor alpha-induced and protein kinase C (PKC)-dependent activation of NF-kappa B, and inhibitors of Tat and NF-kappa B cooperatively down-regulate this Tat- mediated LTR superactivation. In this study, a combined pharmacologic and genetic strategy using two PKC (NF-kappa B) inhibitors, pentoxifylline (PTX) and Go-6976, and a stably expressed anti-Tat single-chain intracellular antibody (sFv intrabody) was employed to obtain cooperative inhibition of both HIV-1 LTR-driven gene expression and HIV-1 replication. Treatment of cells with PTX and Go-6976 resulted in cooperative inhibition of both HIV-1 LTR-driven gene expression and HIV-1 replication. In addition, the combined use of anti-Tat sFv intrabodies and the two NF-kappa B inhibitors retained the virus in the latent state for as long as 45 days. The combined treatment resulted in more durable inhibition of HIV-1 replication than was seen with the NF- kappa B inhibitors alone or the anti-Tat sFv intrabodies alone. Together, these results suggest that in future clinical gene therapy trials, a combined pharmacologic and genetic strategy like the one reported here may improve the survival of transduced cells and prolong clinical benefit.

This article has been cited by other articles:

• Zhao, C., Papadopoulou, B., Tremblay, M. J. (2004). Leishmania infantum Promotes Replication of HIV Type 1 in Human Lymphoid Tissue Cultured Ex Vivo by Inducing Secretion of the Proinflammatory Cytokines TNF-{alpha} and IL-1{alpha}. J. Immunol. 172: 3086-3093 [Abstract] [Full Text]  
• Bai, J., Sui, J., Zhu, R. Y., Tallarico, A. St. C., Gennari, F., Zhang, D., Marasco, W. A. (2003). Inhibition of Tat-mediated Transactivation and HIV-1 Replication by Human Anti-hCyclinT1 Intrabodies. J. Biol. Chem. 278: 1433-1442 [Abstract] [Full Text]  
• Kaushik, N., Basu, A., Palumbo, P., Myers, R. L., Pandey, V. N. (2002). Anti-TAR Polyamide Nucleotide Analog Conjugated with a Membrane-Permeating Peptide Inhibits Human Immunodeficiency Virus Type 1 Production. J. Virol. 76: 3881-3891 [Abstract] [Full Text]  
• Marschall, M., Stein-Gerlach, M., Freitag, M., Kupfer, R., van den Bogaard, M., Stamminger, T. (2001). Inhibitors of human cytomegalovirus replication drastically reduce the activity of the viral protein kinase pUL97. J. Gen. Virol. 82: 1439-1450 [Abstract] [Full Text]  
• Hasebe, Y., Thomson, L. R., Dorey, C. K. (2000). Pentoxifylline Inhibition of Vasculogenesis in the Neonatal Rat Retina. IOVS 41: 2774-2778 [Abstract] [Full Text]  
• Biswas, D. K., Cruz, A. P., Gansberger, E., Pardee, A. B. (2000). Epidermal growth factor-induced nuclear factor kappa B activation: A major pathway of cell-cycle progression in estrogen-receptor negative breast cancer cells. Proc. Natl. Acad. Sci. USA 97: 8542-8547 [Abstract] [Full Text]  
• Legastelois, I., Desgranges, C. (2000). Design and Intracellular Activity of a Human Single-Chain Antibody to Human Immunodeficiency Virus Type 1 Conserved gp41 Epitope. J. Virol. 74: 5712-5715 [Abstract] [Full Text]  
• Chen, F., Lu, Y., Castranova, V., Rojanasakul, Y., Miyahara, K., Shizuta, Y., Vallyathan, V., Shi, X., Demers, L. M. (1999). Nitric Oxide Inhibits HIV Tat-Induced NF-{kappa}B Activation. Am. J. Pathol. 155: 275-284 [Abstract] [Full Text]  
• Chen, F., Castranova, V., Shi, X., Demers, L. M. (1999). New Insights into the Role of Nuclear Factor-{kappa}B, a Ubiquitous Transcription Factor in the Initiation of Diseases. Clin. Chem. 45: 7-17 [Abstract] [Full Text]