Important note: Information in this article was accurate in November 2002. The state of the art may have changed since the publication date.AIDSWEEKLY Plus; November 11, 2002
Michael Greer, Senior Medical Writer
"The human cyclin T1 (hCycT1) protein from the positive transcription elongation factor b (P-TEFb) binds the transactivator Tat and the transactivation response (TAR) RNA stem loop from human immunodeficiency virus type 1 (HIV)," explained Koh Fujinaga and colleagues at the University of California at San Francisco.
Fujinaga and coauthors found that a dominant-negative fusion protein, comprising mutant versions of hCycT1 and TAR (Cdk9), strongly inhibited HIV activity in human cells.
The researchers initially constructed a mutant form of hCycT1 that was unable to bind Cdk9 efficiently. Although somewhat effective in animal models, this reengineered protein had only marginal impact on HIV gene expression in human cells, they said.
A protein chimera made up of mutant hCycT1 fused with defective Cdk9 produced much better results. This construct potently suppressed Tat activity and viral replication in both animal and human cells, study data showed.
The reengineered version of Cdk9 was kinase inactivated by replacing residues critical for C terminus autophosphorylation (Optimized chimeras between kinase-inactive mutant Cdk9 and truncated cyclin T1 proteins efficiently inhibit Tat transactivation and human immunodeficiency virus gene expression. J Virol 2002 Nov;76(21):10873-81.
"This chimera inhibited Tat transactivation and HIV gene expression in human cells," Fujinaga and colleagues concluded. "Therefore, this dominant-negative kinase-inactive mutant Cdk9.hCycT1 chimera could be used for antiviral gene therapy."
The corresponding author for this report is B. Matija Peterlin, Rm. N225, UCSF-Mt. Zion Cancer Center, 2340 Sutter St., San Francisco, CA 94115, USA. E-mail: matija@itsa.ucsf.edu.
A search at www.NewsRx.net using the search term "AIDS and HIV therapy" yielded 1193 articles in 29 specialized reports.
Key points reported in this study include:
A dominant-negative fusion protein, comprising mutant versions of human cyclin T1 (hCycT1) and Cdk9, strongly inhibits HIV replication
Mutant hCycT1 alone was effective in an animal model but had only limited impact on viral activity in human cells
The fusion protein strongly suppressed HIV Tat activity - and thus viral replication - in both animal and human cells
This article was prepared by AIDS Weekly editors from staff and other reports.
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