Our long-term objective is to obtain a detailed understanding of the structure-function relationships of the tat (trans-activating protein) and art/rev (regulator of expression of virion proteins) proteins of human immunodeficiency virus (HIV), the trans- activating factors essential for the replication of the virus. For the research proposed here, our specific aims are: (1) Total chemical synthesis of the tat and art proteins and their structural analogues by the solid-phase methods. These proteins will be obtained in highly purified form and in sufficient quantity by applying both the stepwise strategy and the segment condensation strategy of peptide synthesis, the latter permitting preparation of analogues of the protein modified specifically at selected amino acid side-chain functions. Availability of chemically homogeneous tat and art proteins will permit studies leading to a better evaluation of their structure-trans-activating function relationship. (2) To determine selectively the role of these proteins on the HIV LTR-directed gene expression, both at the transcriptional and the translational levels. (3) To determine the functional domains by using rabbit antibodies against synthetic peptides representing selected regions of the proteins in competition experiments. (4) Use chemical modification approach to determine the role of side-chain functions of selected amino acid residues in binding to the nucleic acid sequences and to any other functional molecules. The results from these studies will provide an understanding of the elements involved in the tat and art regulated expression of the HIV structural proteins. Such an understanding could provide the basis for a rational chemotherapeutic approach directed against acquired immunodeficiency syndrome (AIDS).
| Kaczmarski, W; Khan, S A (1993) Lupus autoantigen Ku protein binds HIV-1 TAR RNA in vitro. Biochem Biophys Res Commun 196:935-42 |
| Reddy, M V; Desai, M; Jeyapaul, J et al. (1992) Functional analysis of the N-terminal domain of Tat protein of the human immunodeficiency virus type 1. Oncogene 7:1743-8 |
| Jeyapaul, J; Seshamma, T; Khan, S A (1991) Synthetic HIV-1 Tat can dissociate HeLa nuclear protein-TAR RNA complexes in vitro: a novel Tat-nuclear protein interaction. Oncogene 6:1507-13 |
| Jeyapaul, J; Reddy, M R; Khan, S A (1990) Activity of synthetic tat peptides in human immunodeficiency virus type 1 long terminal repeat-promoted transcription in a cell-free system. Proc Natl Acad Sci U S A 87:7030-4 |
