Abstract

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.

Public Health Relevance

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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI104523-01A1
Application #
8534995
Study Section
AIDS Molecular and Cellular Biology Study Section (AMCB)
Program Officer
Sharma, Opendra K
Project Start
2013-02-15
Project End
2013-05-31
Budget Start
2013-02-15
Budget End
2013-05-31
Support Year
1
Fiscal Year
2013
Total Cost
$52,612
Indirect Cost
$22,548

  Institution

Name
Harvard University
Department
Veterinary Sciences
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115

  Publications

Termini, James M; Church, Elizabeth S; Silver, Zachary A et al. (2017) Human Immunodeficiency Virus and Simian Immunodeficiency Virus Maintain High Levels of Infectivity in the Complete Absence of Mucin-Type O-Glycosylation. J Virol 91:
Postler, Thomas S; Pantry, Shara N; Desrosiers, Ronald C et al. (2017) Identification and characterization of a long non-coding RNA up-regulated during HIV-1 infection. Virology 511:30-39
Panico, Maria; Bouché, Laura; Binet, Daniel et al. (2016) Mapping the complete glycoproteome of virion-derived HIV-1 gp120 provides insights into broadly neutralizing antibody binding. Sci Rep 6:32956
Stansell, Elizabeth; Panico, Maria; Canis, Kevin et al. (2015) Gp120 on HIV-1 Virions Lacks O-Linked Carbohydrate. PLoS One 10:e0124784