Highly conserved threonine residues were noted near the C-terminus of the external surface glycoproteins of HIV-1, SIV, and influenza A virus; this threonine residue was shown to be the efficient target of O-glycosylation on all three viruses. In all three cases, this O-glycosylated threonine was essential for the infectivity of the virus. We will define the functional role of C-terminal threonine glycosylation for HIV-1 and we will develop assays amenable to high throughput screening for the development of antiviral drugs. We will delineate protein-peptide and peptide-peptide interactions that are dependent on the O-glycosylated threonine of gp120. We will also examine whether there are rare examples of naturally-occurring HIV-1 sequences that are functional without an O-glycosylated threonine at this location.
Better understanding of the molecular mechanisms of AIDS pathogenesis will eventually fuel new drug and vaccine development efforts. The proposed studies will unravel the biochemical details surrounding a previously unknown post-translational modification that has recently been discovered by the Desrosiers laboratory: O-glycosylation of a highly-conserved C-terminal threonine residue on gp120 of HIV-1 and SIV. This threonine O-glycosylation is required for infectivity of both viruses.
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