Human immunodeficiency virus type I (HIV-1) is the causative agent of acquired immune deficiency syndrome (AIDS). The genome of HIV- 1 is far more complex than that of typical animal retroviruses, containing at least six additional genes encoding both positive and negative regulatory functions. In addition to the usual complement of gag, pol, and env genes, these genes provide the virus with an elaborate superstructure of genetic control elements which govern its replication. Recently, we have identified an additional gene of HIV-1 which we call vpu. The open reading frame for vpu occupies the space immediately following the splice donor site at the end of the first exons of tat and rev, and is capable of encoding a product of approximately 80 amino acids depending upon the particular strain of virus. The goals of this project are to further characterize the product of the vpu gene and to develop an understanding of the role of vpu in the HIV-1 life cycle. The physical-chemical characterization of the gene product will include over-expression, purification, and sequencing of the vpo product examination of possible post-translational modifications and determination of its intracellular localization. The proposed functional studies include detailed replication studies of isogeneic viruses differing only in their ability to express vpu, characterization of the replication of HIV-1 as well as HIV-II, SIV and other viruses within lymphocyte cell lines stably expressing the vpu gene product and a genetic analysis of the functionally important domains within the protein. A much better understanding of the role of vpu is important for several reasons. First, because preliminary evidence indicates that the vpu product serves a regulatory function in the HIV-01 life cycle, it would appear to be a natural target point for therapeutic intervention. In addition, because this reading frame occurs only in HIV-1 and not in the related HIV-2 or SIV viruses, its study may provide an important clue to the divergent patterns of infectivity and virulence observed with these different viruses. Finally, k the genetic regulatory mechanisms revealed by the study of HIV-1 gene expression will likely have important implications for understanding regulation of gene expression in normal eukaryotic cells.
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