Mutational analysis of HIV-1 Tat minimal domain peptides: identification of trans-dominant mutants that suppress HIV-LTR-driven gene expression.

Important note: Information in this article was accurate in 1989. The state of the art may have changed since the publication date.

Mutational analysis of HIV-1 Tat minimal domain peptides: identification of trans-dominant mutants that suppress HIV-LTR-driven gene expression.

Cell. 1989 Jul 14;58(1):215-23. Unique Identifier : AIDSLINE MED/89324055
Green M; Ishino M; Loewenstein PM; Institute for Molecular Virology, St. Louis University School of; Medicine, Missouri 63110.

Abstract: The HIV-1 Tat protein is a potent trans-activator essential for virus replication. We reported previously that HIV-1 Tat peptides containing residues 37-48 (mainly region II), a possible activating region, and residues 49-57 (region III), a nuclear targeting and putative nucleic acid binding region, possess minimal but distinct trans-activator activity. The presence of residues 58-72 (region IV) greatly enhances trans-activation. We postulate that Tat mutant peptides with an inactive region II and a functional region III can behave as dominant negative mutants. We synthesized minimal domain peptides containing single amino substitutions for amino acid residues within region II that are conserved among different HIV isolates. We identify four amino acid residues whose substitution within Tat minimal domain peptides leads to defects in transactivation. Some of these mutants are trans-dominant in several peptide backbones, since they strongly inhibit trans-activation by wild-type Tat protein added to cells or expressed from microinjected plasmid. Significantly, trans-activation of integrated HIV-LTRCAT is blocked by some trans-dominant mutant peptides. These results suggest an attractive approach for the development of an AIDS therapy.

Keywords: Amino Acid Sequence DNA Mutational Analysis Gene Expression Regulation Genes, Dominant HIV/*GENETICS Molecular Sequence Data Regulatory Sequences, Nucleic Acid Repetitive Sequences, Nucleic Acid Retroviridae Proteins/*GENETICS Structure-Activity Relationship Support, U.S. Gov't, P.H.S. Transcription Factors/*GENETICS Transcription, Genetic JOURNAL ARTICLE

891130
M89B0523

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