The envelope glycoprotein of human immunodeficiency virus (HIV) functions in the early events in virus replication, and is also required for the assembly of infectious progeny virions. In this project, we have proposed strategies for the identification of novel inhibitors which affect the synthesis, transport or function of HIV glycoproteins. Many of the experimental approaches are based upon our knowledge of the biosynthesis, transport and function of membrane glycoproteins of other enveloped viruses.
The specific aims of the proposal are: 1. To synthesize a series of peptides corresponding to the N- terminus of gp41, and evaluate the effects of these peptides on HIV replication and virus-induced cell fusion. The sequence specificity of the inhibitory effect of these peptides will be investigated by using a series of different virus isolates which exhibit variation in the N-terminal sequences of gp41. 2. To investigate the effects of known as well as novel glycosylation inhibitors upon HIV envelope protein glycosylation, oligosaccharide processing, and transport to the cell surface. The receptor-binding and fusion activities of glycoproteins with modified oligosaccharides will be determined. 3. To investigate the effects of anti-sense RNA sequences directed against HIV envelope genes on the replication, assembly and release of HIV. 4. To determine the effects of inhibitors on the assembly of HIV virions. Virusinfected cells will be treated with compounds found to suppress virus replication, and such cells will be embedded and examined by electron microscopy to determine any effects on core assembly, virus budding, and virus release.
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